PT1656361E - Piperazine with or-substituted phenyl group and their use as glyt1 inhibitors - Google Patents

Piperazine with or-substituted phenyl group and their use as glyt1 inhibitors Download PDF

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PT1656361E
PT1656361E PT04763703T PT04763703T PT1656361E PT 1656361 E PT1656361 E PT 1656361E PT 04763703 T PT04763703 T PT 04763703T PT 04763703 T PT04763703 T PT 04763703T PT 1656361 E PT1656361 E PT 1656361E
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phenyl
piperazin
methanesulfonyl
fluoro
methanone
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PT04763703T
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Portuguese (pt)
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Emmanuel Pinard
Synese Jolidon
Matthias Heinrich Nettekoven
Robert Narquizian
Roger David Norcross
Stalder Henri
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Hoffmann La Roche
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

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Description

DESCRIÇÃO PIPERAZINA COM UM GRUPO FENILO SUBSTITUÍDO DO TIPO OR E A SUA UTILIZAÇÃO COMO INIBIDOR DE TGLIl A presente invenção tem por objecto compostos de fórmula (I)The present invention relates to compounds of the formula (I) wherein R 1 and R 2 are as defined in formula (I)

O oOo

em queon what

Ar representa arilo substituído ou insubstituído ou heteroarilo com 6 átomos no núcleo, contendo um, dois ou três átomos de azoto e em que os grupos arilo e heteroarilo podem estar substituídos por um ou mais substituintes seleccionados do grupo que consiste em hidrogénio, halogéneo, N02CN, alquilo Ci-C6,- alquilo C1-C6 substituído por halogéneo, alquilo C1-C6 substituído por hidroxi, (CH2) n-alcoxi Ci-Cg, alcoxi Ci-Cg substituído por halogéneo, NR7R8, C(0)R9, SO2R10, -0((¾) =NOR7 ou por um heterociclo aromático com 5 átomos no núcleo contendo 1-4 heteroátomos, seleccionados entre N e 0, que está eventualmente substituído por alquilo Ci-Cg; R1 representa hidrogénio ou alquilo Ci-C6; 1 R2 representa hidrogénio ou alquilo Cj-Cg, alcenilo C2-Cg, alquilo Ci-Cg substituído por halogéneo, alquilo Ci-Cê substituído por hidroxi; {CH2) n~cicloalquilo C3-C7 eventualmente substituído por alcoxi Ci~Ce ou por halogéneo ou representa CH (CH3)-cicloalquilo C3-C7, (CH2)n+i-C (0) R9, (CH2}n+i-CN, bibiclo[2.2.1]-heptilo, - (CH2) n+i-O-alquilo Ci-Cô, (CH2) n-heterociclõalquilo, (CH2)n-arilo ou (CH2) n-heteroarilo com 5 ou 6 átomos no núcleo contendo um, dois ou três heteroátomos se-leccionados no grupo que consiste em oxigénio, enxofre ou azoto em que arilo, heterocicloâlquilo e heteroa-rilo estão' insubstituídos ou substituídos por um ou mais substituintes seleccionados no grupo que consiste em hidroxi, halogéneo, alquilo Ci-Cg ou alcoxi Ci-Cg; R3, R4 e R6 representam, independentemente uns dos outros, hidrogénio, hidroxi, halogéneo, alquilo Ci~C6 ou alcoxi Ci~C6 ou O-cicloalquilo C3-C6; R5 representa N02, CN, C(0)R9 ou S02R10; R7 e R8 representam, independentemente um do outro, hidrogénio ou alquilo Ci-Cg; R9 representa hidrogénio, alquilo Ci-Cg, alcoxi Ci-Cç ou NR7R8; R10 representa alquilo Ci-Cg eventualmente substituído por halogéneo, (CH2}n“CÍcloalquilo C3"C6, (CH2)n- alcoxi C3-C6, (CH2)n-heterocicloalquilo ou NR7R8; n representa 0, 1, ou 2; 2 e os seus sais de adição de ácido aceitáveis sob o ponto de vista farmacêutico, com a condição de que 1-[5- (amino-sulfonil)-2-metoxibenzoil]-4-(3-clorofe-nil)-piperazina, l-[5-(amino-sulfonil)-2-metoxibenzoil]-4-(4-fluorofe-nil)-piperazina, 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-[3-(trifluo-rometil)fenil]-piperazina, 4-(3-amino-4-nitrofenil)-1-[4-(dimetilamino) -2^-me-toxi-5-nitrobenzoil]-2-metilpiperazina, 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-4-(4-nitrofenil)-piperazina, 4- [4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-l-(4-nitrofenil)-piperazina, 1-(2-cloro-4-nitrofenil)-4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-piperazina, 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-4-(2,4-dinitrofenil)-2-metil-piperazina, 1-(4-cloro-2-nitrofenil)-4-[4-(dimetilamino)-2-metoxi- 5- nitrobenzoil]-piperazina 4- [4- (dimetilamino.) -2-metoxi-5-nitrobenzoil] -1- (2,4-dinit.rofenil)-2-metil-piperazina e 1- ['(2-benziloxi-5-formi.l) benzoil] -4-fenilpiperazina estejam excluídos.Ar represents substituted or unsubstituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms and wherein the aryl and heteroaryl groups may be substituted by one or more substituents selected from the group consisting of hydrogen, halogen, NO 2 CN C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, C 1 -C 6 alkyl substituted by hydroxy, (CH 2) n -C 1 -C 6 alkoxy, halogen substituted C 1 -C 6 alkoxy, NR 7 R 8, C (O) R 9, SO 2 R 10 , -O (O) = NOR7 or by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by C 1 -C 6 alkyl, R 1 represents hydrogen or C 1 -C 6 alkyl; R 2 represents hydrogen or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl substituted by halogen, C 1 -C 6 alkyl substituted by hydroxy, (CH 2) n C 3 -C 7 cycloalkyl optionally substituted by C 1 -C 10 alkoxy or by halogen or represents CH (CH 3) -C 3 -C 7 cycloalkyl, (CH 2) n + i (CH2) n - (CH2) n - (CH2) n - (CH3) n - (CH2) n - aryl or (CH 2) n-heteroaryl having 5 or 6 ring atoms containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen in which aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C1 -C6 alkyl or C1 -C6 alkoxy; R 3, R 4 and R 6 independently of one another represent hydrogen, hydroxy, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy or O-C 3 -C 6 cycloalkyl; R 5 represents NO 2, CN, C (O) R 9 or SO 2 R 10; R 7 and R 8 represent, independently of one another, hydrogen or C 1 -C 6 alkyl; R9 represents hydrogen, C1 -C6 alkyl, C1 -C6 alkoxy or NR7 R8; R10 represents C1-6 alkyl optionally substituted by halogen, (CH2) n C3 cycloalkyl, C6, (CH2) n C3-C6 alkoxy, (CH2) n-heterocycloalkyl or NR7 R8, n represents 0, 1, or 2; and the pharmaceutically acceptable acid addition salts thereof with the proviso that 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chloro-phenyl) -piperazine, 1 - [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (4-fluorophenyl) piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- [3- (trifluoromethyl) 4-nitrophenyl) -1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methylpiperazine, 1- [4- (3-amino- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl-4- (4-nitrophenyl) piperazine, 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2- - (4-nitrophenyl) -piperazine, 1- (2-chloro-4-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -piperazine, 1- [4- (dimethylamino) 2-methoxy-5-nitrobenzoyl] -4- (2,4-dinitrophenyl) -2-methylpiperazine, 1- (4-chloro-2-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy- 5-nitrobenzoyl] -1- (2,4-dinitrophenyl) -2-methylpiperazine and 1- [2- (2-methoxyphenyl) benzyloxy-5-formyl) benzoyl] -4-phenylpiperazine are excluded.

Os compostos 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-(3-clorofe-nil)-piperazina, 1- [5- (amino-sulfonil) -2-metoxibenzoil] -4- ('4-fluoro-fenil)-piperazina e 3 1- [5-(amino-sulfonil)-2-metoxibenzoil]-4-[3-(trifluoro- metil)fenil]-piperazina estão especificamente descritos na EP 0171636, possuindo actividade inibidora em relação à anidrãse carbónica que desempenha um papel determinante em muitos processos fisiológicos e patológicos. Os outros compostos excluídos são produtos disponíveis comercialmente. O composto excluído 1-[(2-benziloxi-5-formil)benzoil]-4-fenilpiperazi-na já foi descrito na patente WO 02/22612 para ser utilizado na profilaxia ou no tratamento de infecçóes provocadas por fungos. No Journal of Medicinal Chemistry, Vol. 44, No. 17, 2679 - 2682, (2001) e patente WO 99/45011 estão descritos compostos estruturalmente distintos com actividade inibidora dos transportadores de glicina. Na Database Chemcats, descreve-se o composto piperazina, 1-{9H-fluoren-9-il)-4-[2-(4-metoxifenoxi)-5-nitroben-zoil] contudo não foi descrita nenhuma actividade farmacêutica. A presente invenção tem por objecto compostos de fórmula geral I, composições farmacêuticas que o contêm e a sua utilização no tratamento de distúrbios neurológicos e neuropsiquiátricos. Tem-se vindo a verificar, surpreendentemente que os compostos de fórmula geral I são inibidores do transportador 1 de glicina (TGli-1, GlyT-1 ha terminologia inglesa) e que têm uma boa selectividade para os inibidores do transportador 2 de glicina (TG.li-2),. A esquizofrenia é uma doença neurológica progressiva e devastadora caracterizada por sintomas positivos episódicos tal como ilusões, alucinações, distúrbios do pensamento e psicoses e sintomas negativos persistentes tais como afectos enfraquecidos, atenção defeituosa e afastamento social e distúrbios cognitivos (Lewis DA. e Lieberman JA, Neuron, 28: 325-33, 2000). Durante décadas a investi- 4 gação focou-se nas hipóteses de "hiperactividade dopami-nérgica". que tem levado a intervenções terapêuticas que envolvem o bloqueio do sistema dopaminérgico (Vandenberg RJ e Aubrey KR., Exp. Opin. Ther. Targets, 5 (4): 507-518, 2001; Nakazato A e Okuyama S, et al., Exp. Opin. Ther. Patents, 10 (1): 75-98, 2000). Esta abordagem farmacológica dirige-se vagamente a sintomas negativos e cognitivos que são os melhores factores preditivos dos resultados funcionais (Sharma T., Br. J. Psychiatry, 174 (supl. 28): 44-51, 1999) .The compounds 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chlorophenyl) piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (' 4-fluoro-phenyl) -piperazine and 3- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- [3- (trifluoromethyl) phenyl] -piperazine are specifically described in EP 0171636, having inhibitory activity in relation to carbonic anhydride which plays a determining role in many physiological and pathological processes. The other excluded compounds are commercially available products. The compound excluded 1 - [(2-benzyloxy-5-formyl) benzoyl] -4-phenylpiperazinone has already been described in WO 02/22612 for use in the prophylaxis or treatment of fungal infections. In the Journal of Medicinal Chemistry, Vol. 44, No. 17, 2679-2682, (2001) and WO 99/45011 are described structurally distinct compounds with inhibitory activity of the glycine transporters. In Database Chemcats, the piperazine compound, 1- (9H-fluoren-9-yl) -4- [2- (4-methoxyphenoxy) -5-nitrobenzoyl] is described, however no pharmaceutical activity has been described. The present invention provides compounds of general formula I, pharmaceutical compositions containing it and their use in the treatment of neurological and neuropsychiatric disorders. It has surprisingly been found that the compounds of formula I are inhibitors of glycine transporter 1 (TGli-1, GlyT-1, English terminology) and which have good selectivity for inhibitors of glycine transporter 2 (TG .li-2). Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, disturbances of thought and psychoses, and persistent negative symptoms such as weakened affections, faulty attention and social withdrawal, and cognitive disorders (Lewis DA and Lieberman JA, Neuron, 28: 325-33, 2000). For decades research has focused on the hypotheses of " dopaminergic hyperactivity ". which has led to therapeutic interventions involving dopaminergic system blockade (Vandenberg RJ and Aubrey KR, Exp. Opin. Ther. Targets, 5 (4): 507-518, 2001. Nakazato A and Okuyama S, et al. Exp. Opin Ther. Patents, 10 (1): 75-98, 2000). This pharmacological approach loosely targets negative and cognitive symptoms that are the best predictive factors of functional outcomes (Sharma T., Br. J. Psychiatry, 174 (Suppl 28: 44-51, 1999).

Um modelo complementar de esquizofrenia foi proposto em meados de 1960 com base na acção psicotomimética causada pelo bloqueio do sistema de glutamato por meio de compostos como fenciclidina (PCP) e agentes relacionados (cetamina) que são antagonistas não 'concorrenciais do receptor de NMDA (ácido N-metil-D-aspártico). É interessante que, em voluntários saudáveis, a acção psicotomimética induzida por PCP incorpora sintomas positivos e negativos assim como disfunção cognitiva, assemelhando-se assim fortemente à esquizofrenia em pacientes (Javitt D.C. et al.r Biol. Psychiatry, 45: .668-679, 1999). Além disso, ratos transgénicos que expressam níveis reduzidos da sub-unidade NMSAR1 exibem compostamentos anormais semelhantes aos observados em modelos de esquizofrenia, induzidos farmacologicamente, suportando um modelo em que a reduzida actividade receptora de NMDA resulta num comportamento semelhante à esquizofrenia (Mohn A.R. et al.r Cell, 98: 427-236, 1999). A neurotransmissão do glutamato, em particular a actividade do receptor de NMDA, desempenha um papel crítico na plasticidade sináptica, aprendizagem e memória, tal como os receptores de NMDA parecem servir como um interruptor 5 graduado para bloquear o limiar da plasticidade sináptica e da formação da memória (Wiley, NY; Bliss TV e Collingridge GL, Nature, 361: 31-39, 1993). Os ratos transgénicos que sobre-expressam a sub-unidade NR2B de NMDA exibe uma maior ' plasticidade sináptica e uma capacidade superior de aprendizagem e da memória (Tang JP et al., Natur,. 401- 63-69, 1999). Assim, se a falta de glutamato está implicada na patofisiologia da esquizofrenia, o aumento da transmissão do glutamato, em particular por via da activação do receptor de NMDA, previsivelmente deveria produzir efeitos de melhoria tanto anti-psicóticos como cognitivos. O aminoácido glicina é conhecido por ter pelo menos duas funções importantes no SNC (sistema nervoso central). Actua como um aminoácido inibidor, ligando-se a receptores de glicina sensíveis a estriquinina e também influencia a actividade excitadora, actuando como um co-agonista essencial com glutamato para a função receptora do N-metil-D-aspartato (NMDA). Enquanto o glutamato é libertado de uma forma dependente da actividade a partir de terminais sinápticos, a glicina está presente, aparentemente, num nível maís constante e parece modular/controlaro receptor para a sua resposta ao glutamato. Uma das vias mais efectivas para controlar as concentrações sinápticas do neurotransmissor consiste em influenciar a sua reabsorção nas sinapses. Os transportadores de neurotransmissores, removendo os neurotran-smissores do espaço ectracelular, podem controlar o seu tempo de vida extracelular e assim. modular a dimensão da transmissão sináptica (Gainetdinov RR et al, Trends in Pharm. Sei., 23 (8): 367-373, 2002).A complementary model of schizophrenia was proposed in the mid-1960s based on the psychotomimetic action caused by the blockade of the glutamate system by compounds such as phencyclidine (PCP) and related agents (ketamine) that are noncompetitive antagonists of the NMDA receptor N-methyl-D-aspartic acid). Interestingly, in healthy volunteers, PCP-induced psychotomimetic action incorporates both positive and negative symptoms as well as cognitive dysfunction, thus strongly resembling schizophrenia in patients (Javitt DC et al., Biol. Psychiatry, 45: 668-679 , 1999). In addition, transgenic mice expressing reduced levels of the NMSAR1 subunit exhibit abnormal compostats similar to those observed in pharmacologically induced schizophrenia models, supporting a model in which reduced NMDA receptor activity results in a behavior similar to schizophrenia (Mohn AR et al. Cell, 98: 427-236 (1999)). Neurotransmission of glutamate, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning, and memory, just as NMDA receptors appear to serve as a graduated switch to block the threshold of synaptic plasticity and memory (Wiley, NY; Bliss TV and Collingridge GL, Nature, 361: 31-39, 1993). Transgenic mice overexpressing the NMDA NR2B subunit exhibit increased synaptic plasticity and superior learning and memory capacity (Tang JP et al., Nature, 401- 63-69, 1999). Thus, if the lack of glutamate is implicated in the pathophysiology of schizophrenia, increased glutamate transmission, in particular via activation of the NMDA receptor, should predictably produce both antipsychotic and cognitive enhancement effects. The amino acid glycine is known to have at least two important functions in the CNS (central nervous system). It acts as an inhibitory amino acid, binding to estrikinin-sensitive glycine receptors and also influences the excitatory activity, acting as an essential co-agonist with glutamate for the N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a constant level and appears to modulate / control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of the neurotransmitter is to influence its reabsorption at the synapses. Neurotransmitter transporters, removing neurotransmitters from the ectracellular space, can control their extracellular lifespan and thus. modulating the size of the synaptic transmission (Gainetdinov RR et al, Trends in Pharm, Sci., 23 (8): 367-373, 2002).

Os transportadores de glicina, que fazem parte da família do sódio e do cloro dos transportadores de neurotransmissores, desempenham um importante papel na termina- 6 ção de acções glicinérgicas post-sinápticas e na manutenção de concentrações baixas da glicina extracelular por reabsorção da glicina nos terminais de nervos pré-sinápticos e nos processos circundantes da glial fina. Já se clonaram dois genes distintos transportadores de glicina (TGli-1 e TGli-2) do cérebro de mamífero,, que dá origem a dois transportadores com uma homologia da sequência de aminoácidos de ~50 %. TGli-1 apresenta quatro isoformas que resultam da montagem alternativa de genes e da utilização alternativa de promotores (la, lb, lc e Id) . Apenas duas destas isoformas foram encontradas no cérebro de roedores (TGli-la e TGli-lb). TGli-2 também apresenta algum grau de heterogeneidade. Identificaram-se duas isoformas de TGli-2 (2a e 2b) em cérebros, de ratos. TGli-1 é conhecido por estar localizado no SNC e nos tecidos periféricos, enquanto TGli-2 é específico do SNC. TGli-1 tem uma distribuição predominante no glial e encontra-se não apenas e encontra-se não apenas nas áreas que correspondem à modulação da função do receptor de NMDA (Lopez-Corcuera B et al., Mol. Mem. Biol., 18: 13-20, 2001)_. Assim, uma estratégia para aumentar a. actividade de NMDA consiste em elevar a concentração de glicina 'no micro-ambiente local dos receptores sinápticos de NMDA por inibição do transportador TGli-1 (Bergereon R. et al., Proc. Natl. Acad. Sei. EUA, 95: 15730-15734, 1998; Chen L. e al., J. Neurophysiol., 89 (2): 691-703, 2003. Os inibidores dos transportadores de glicina são apropriados para o tratamento de distúrbios neurológicos e neuropsi-quiátricos. A maioria dos estados de doença implicados são as psicoses, a esquizofrenia (Armer RE e Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), os distúrbios psicóticos do humor tal como distúrbios de depressão clínica severa, distúrbios do humor associados com distúr- 7 bios psicóticos tais como .mania aguda ou depressão, associadas com distúrbios bipolares e distúrbios do humor, associados com esquizofrenia (Pralong ET et al., Prog. Neurobiol., 67: 173-202, 2002), distúrbios autistas (Carlsson ML, J. Neural Trans, 105: 525-535, 1998), distúrbios sognitivos tais como demências, incluindo a demência relacionada com a idade e a demência senil do tipo Alzheimer, distúrbios da memória em mamíferos, incluindo em seres humanos, distúrbios de falta de atenção e dor (Armer RE e Miller D J, Exp. Opin. Ther. PatentSr H (4) : 563-572,' 2001). Assim, o aumento da activação dos receptores de NMDA por via da inibição de TGli-1 pode levar a agentes que tratam a psicose, esquizofrenia, demência e outras doenças em que estão envolvidos processos cognitivos, tais como distúrbios de falta de atenção ou doença de Alzheimer.Glycine transporters, which are part of the sodium and chlorine family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and the maintenance of low extracellular glycine concentrations by glycine reabsorption at the terminals of presynaptic nerves and in the processes surrounding the fine glial. Two distinct glycine (TGli-1 and TGli-2) glycine transporter genes have been cloned into the mammalian brain, which gives rise to two transporters with ~ 50% amino acid sequence homology. TGli-1 shows four isoforms resulting from alternative assembly of genes and the alternative use of promoters (la, lb, lc and Id). Only two of these isoforms were found in the brain of rodents (TGli-a and TGli-lb). TGli-2 also shows some degree of heterogeneity. Two isoforms of TGli-2 (2a and 2b) were identified in rats' brains. TGli-1 is known to be located in the CNS and peripheral tissues, while TGli-2 is CNS-specific. TGli-1 has a predominant distribution in glial and is found not only and is found not only in the areas corresponding to the modulation of NMDA receptor function (Lopez-Corcuera B et al., Mol. Mem. Biol., 18 : 13-20, 2001). Thus, a strategy to increase the. NMDA activity is to raise the glycine concentration in the local microenvironment of NMDA synaptic receptors by inhibition of the TGII-1 transporter (Bergereon R. et al., Proc Natl Acad Sci USA 95: 15730- Chen L. et al., J. Neurophysiol., 89 (2): 691-703, 2003. Glycine transporters inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. (Armer RE and Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as disorders of severe clinical depression, disorders associated with psychotic disorders such as acute or severe depression, associated with bipolar disorders and mood disorders, associated with schizophrenia (Pralong ET et al., Prog. Neurobiol., 67: 173-202, 2002), autistic disorders (Carlsson ML, J. Neural Trans, 105: 525-535, 1998), disorders such as dementias, including age-related dementia and senile dementia of the Alzheimer type, memory disorders in mammals, including in humans, disorders of inattention and pain (Armer RE and Miller D J, Exp. Opin. The R. PatentSr H (4): 563-572 (2001). Thus, increased activation of NMDA receptors via the inhibition of TGli-1 can lead to agents treating psychosis, schizophrenia, dementia, and other diseases in which cognitive processes, such as attention-deficit disorders or Alzheimer's disease.

Constituem objectos da presente invenção os compostos de fórmula I per se, a utilização de compostos de fórmula I e os seus sais aceitáveis sob o ponto de vista farmacêutico para o fabrico de medicamentos para o tratamento de doenças relacionadas com a activação dos receptores de NMDA por via da " inibição de TGli-1, o seu' fabrico, medicamentos à base do composto de acordo com a presente invenção e a sua produção assim como a utilização de compostos de fórmula I no controlo ou prevenção de doenças tais como psicoses, disfunção da memória e da aprendizagem, esquizofrenia, demência e outras doenças em que estão envolvidos processos cognitivos, tal como distúrbios do déficit da atenção ou doença de Alzheimer.Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to the activation of NMDA receptors by via " inhibition of TGI-1, their manufacture, medicaments based on the compound of the present invention and their production as well as the use of compounds of formula I in the control or prevention of diseases such as psychoses, memory dysfunction and learning, schizophrenia, dementia and other diseases in which cognitive processes are involved, such as attention deficit disorders or Alzheimer's disease.

As indicações preferidas para a utilização dos compostos dá presente invenção são a esquizofrenia, o 8 envolvimento cognitivo e a doença de Alzheimer. Além disso, a presente invenção inclui todas as misturas racémicas, todos os seus enantiómeros e/ou isómeros ópticos correspondentes.Preferred indications for the use of the compounds of the present invention are schizophrenia, cognitive involvement and Alzheimer's disease. In addition, the present invention includes all racemic mixtures, all of their enantiomers and / or corresponding optical isomers.

Tal como se utiliza aqui, o termo "alquilo" denota um grupo de cadeia linear ou cadeia ramificada.contendo de 1 a 6 átomos de carbono, por exemplo, metilo, etilo, propilo, isopropilo, n-butilo, i-butilo, 2-butilo, t-butilo e similares. Os grupos de alquilo preferidos são os grupos com 1-4 átomos de carbono. 0 termo "halogéneo" indica cloro, iodo, flúor e bromo. 0 termo "arilo" índica um radical de hidrocarboneto aromático cíclico monovalente que consiste em um ou mais. anéis fundidos em que pelo menos -um anel é aromático na sua natureza, escolhidos entre fenilo, benzilo, naftilo, bifenilo ou indanilo. .· A expressão "heteroarilo com 6 átomos no núcleo contendo um, dois ou três átomos de azoto" indica um radical carbociclico aromático,'monovalente, por exemplo, piridilo, pirazinilo, pirimidinilo, piridazinilo ou 1,3,5-triazinilo. 0 termo "heterocicloalqu.ilo" indica um radical de hidrocarboneto não aromático, por exemplo, oxetanilo, tetra-hidrofuranilo, tetra-hidropiranilo, azetidinilo, pirrolidinilo, piperidinilo, piperazinilo, morfolinilo pu tiomorfolinilo. 9 A expressão "heterociclo aromático com 5 átomos no núcleo, contendo 1-4 heteroátomos, seleccionados entre N e 0" indica, por exemplo, 1,2,4-oxadiazolilo, oxazolilo, 1,3,4-oxadiazolilo ou tetrazolilo. A expressão "heteroarilo com 5 ou 6 átomos no núcleo contendo um, dois ou três heteroátomos, seleccionados no grupo que consiste em oxigénio, enxofre ou azoto" indica um radical carbocíclico aromático, monovalente, por exemplo piridilo, pirazinilo, pirimidinilo, piridazinilo, triazinilo, tiazolilo, tienilo, furilo, pirrolilo, imida-zolilo, pirazolilo, isotiazolilo ou isoxazolilo. 0 termo "alquilo, substituído por halogéneo" indica, por exemplo, os seguintes grupos: CF3, CHF.2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CH2CF3, CH2CH2C1, CH2CF2CF3, CH2CF2CHF2, CF2CHFCF3, C(CH3)2CF3, CH(CH3)CF3 ou CH (CH2F) CH2F. A expressão "alquilo, substituído por hidroxi" indica, por exemplo, os seguintes grupos: CH (0H)CH3, ch2ch (oh) ch3, ch2ch(ch3) çh2oh, {CH2)2OH, (CH2}30H ou CH2C[ (CH3) ]2-CH2OH. A expressão "sais de adição de ácidos aceitáveis sob o ponto de vista farmacêutico" engloba sais com ácidos inorgânicos e orgânicos, tais como ácido clorídrico, ácido nítrico, ácido fosfórico, ácido cítrico, ácido fórmico, ácido fumárico, ácido maieico, ácido acético, ácido succínico, ácido tartárico, ácido metano-sulfó-nico, ácido p-tolueno-sulfónico e similares.As used herein, the term " alkyl " denotes a straight chain or branched chain group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are the groups having 1-4 carbon atoms. The term " halogen " indicates chlorine, iodine, fluorine and bromine. The term " aryl " denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more. fused rings in which at least one ring is aromatic in nature, chosen from phenyl, benzyl, naphthyl, biphenyl or indanyl. The term " 6-membered heteroaryl containing one, two or three nitrogen atoms " indicates an aromatic, monovalent, e.g. pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or 1,3,5-triazinyl carbocyclic radical. The term " heterocycloalkyl " indicates a non-aromatic hydrocarbon radical, for example, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or pyromorpholinyl. The term " aromatic heterocycle having 5 atoms in the nucleus, containing 1-4 heteroatoms selected from N and O " indicates, for example, 1,2,4-oxadiazolyl, oxazolyl, 1,3,4-oxadiazolyl or tetrazolyl. The term " 5- or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen " indicates an aromatic, monovalent carbocyclic radical, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl or isoxazolyl. The term " alkyl, substituted by halogen " for example, the following groups: CF 3, CHF 2, CH 2 F, CH 2 CF 3, CH 2 CHF 2, CH 2 CH 2 F, CH 2 CH 2 CF 3, CH 2 CH 2 CH 2 CF 3, CH 2 CH 2 CF 3, CH 2 CHF 2 CF 3, CH 2 CF 2 CHF 2, CF 2 CHF 3, C (CH 3) 2 CF 3, CH (CH 3) ) CH2F. The term " alkyl, substituted by hydroxy " for example, the following groups: CH (OH) CH3, ch2ch (oh) ch3, ch2ch (ch3) hh2oh, (CH2) 2 OH, (CH2) 30H or CH2C [(CH3)] 2 -CH2 OH. ; pharmaceutically acceptable acid addition salts include salts with inorganic and organic acids such as hydrochloric acid, nitric acid, phosphoric acid, citric acid, formic acid, fumaric acid, malonic acid, acetic acid, succinic acid , tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

Um enquadramento da presente invenção consiste nos compostos de fórmula geral 10An embodiment of the present invention consists of the compounds of formula

em queon what

Ar representa arilo substituído ou heteroarilo substituído ou insubstituído com 6 átomos no . núcleo, contendo um, dois ou três átomos de azoto e em que os grupos arilo e heteroarilo podem estar substituídos por um ou mais substituintes seleccionados do grupo que consiste em hidrogénio, halogéneo, N02, CM, alquilo Cx-Cg, alquilo Cx-Cg substituído por halogéneo, alcoxi Cx-Cg, alcoxi Cx-C6 substituído por halogéneo, NR7R8, C(0)R9 ou S02R10; R1 representa hidrogénio ou alquilo Ci-C6; R2 representa alquilo Cx-Cg, alquilo Cx-C6 substituído por halogéneo, cicloalquilo C3-C6,heterocicloalquilo, (alquil Cx-Cê) -cicloaquilo C3-C6, (alquil Cx-Cg) -heterocicloalquilo, (alquil Οχ-Cs)-C (0)-R9, (alquil Ci-Cg)-CN, (alquil C2-C6)-0-R13, (alquil C2-Cg)-NR7RS, arilo ou heteroarilo com 6 átomos no núcleo contendo um, dois ou três átomos de azoto, (alquil Cx-Cg)- arilo ou (alquil Cx-Cs)- heteroarilo com 5 ou 6 átomos no núcleo contendo um, dois ou três heteroátomos seleccionados no grupo que consiste em oxigénio, enxofre ou azoto em que arilo, heterocicloalquilo e heteroarilo estão _’p.. insubstituídos ou substituídos por um ou mais substituintes seleccionado no grupo que consiste em hidroxi,". halogéneo, alquilo Cx-Cç ou alcoxi Οχ-Cg; 11 R3, R4 e R6 representam, independentemente uns dos outros, hidrogénio, hidroxi, halogéneo, CN, alquilo Ci-Ce, alcoxi Ci-C6 ou NR7R8; R5 -representa N02, CN, C(0)R9, S02R10 ou NR11R12; R7 e. R8 representam, independentemente uns dos outros, hidrogénio ou alquilo Ci-C6; R9 representa hidrogénio, àlquilO Ci-Cs, cicloalquilo C3-C6, alcoxi Ci-C6 ou NR7R8,' R10 representa alquilo C;l-C6, cicloalquilo C3-C6, ou NR7R8; ^ R11 e R12 representam, independentemente um do outro, hidrogénio, C(0)-alquilo C1-C6, S02- alquilo Ci-C6, ou formam em conjunto com o átomo de N um grupo heteroarilo com 5 átomos no núcleo, eventualmente substituído por halogéneo, alquilo C1-C6, alquilo Ci~ C6 substituído por halogéneo, ou cicloalquilo C3-C6; R13 represènta hidroxi, alquilo C1-C6 ou cicloalquilo C3-C5; e os seus sais de adição de ácido aceitáveis sob o ponto de vista farmacêutico, com a condição de que . 1- [5-(amino-sulfonil)-2-metoxibenzoil]-4-(3-clorofe-.nil)-piperazina, 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-(4-fluorofe-nil)-piperazina, 1- [5-(amino-sulfonil)-2-metoxibenzoil]-4-[3-(trifluo-rometil)fenil]-piperazina, 12 4-(3-amino-4-nitrofenil)-1-[4-(dimetilamino)-2-me-toxi-5-nitrobenzoil] -2-metilpiperazina, 1-[4-(dimetilamino)-2-inetoxi-5-nitrobenzoil]-2-metil-4-(4-nitrofenil)-piperazina, 4- [4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-l-(4-nitrofenil)-piperazina, 1- (2-cloro-4-nitrofenil)-4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-piperazina, 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-4-(2,4-dinitrofenil)-2-metil-piperazina, 1-(4-cloro-2-nitrofenil)-4-[4-(dimetilamino)-2-metoxi- 5- nitrobenzoil]-piperazina 4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-1-(2,4-dinitrofenil)-2-metil-piperazina e 1-[(2-benziloxi-5-formil)benzoil]-4-fenilpiperazina estejam excluídas.Ar represents substituted aryl or substituted or unsubstituted heteroaryl having 6 carbon atoms. nucleus having one, two or three nitrogen atoms and wherein the aryl and heteroaryl groups may be substituted by one or more substituents selected from the group consisting of hydrogen, halogen, NO2, CN, C1 -C6 alkyl, C1 -C6 alkyl substituted by halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by halogen, NR 7 R 8, C (O) R 9 or SO 2 R 10; R 1 represents hydrogen or C 1 -C 6 alkyl; R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, C 3 -C 6 cycloalkyl, heterocycloalkyl, (C 1 -C 6) alkyl-C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl) -heterocycloalkyl, (C 1 -C 8 alkyl) C (O) -R 9, (C 1 -C 6 alkyl) -CN, (C 2 -C 6) alkyl-O-R 13, (C 2 -C 6 alkyl) -NR 7 RS, aryl or 6-membered heteroaryl containing one, two or three (C 1 -C 6) alkyl-aryl or (C 1 -C 6) alkyl-heteroaryl having 5 or 6 ring atoms containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen in which aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, ". halogen, C1 -C6 alkyl or Câ, -Câ, "alkoxy; R 4, R 4 and R 6 independently of one another are hydrogen, hydroxy, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or NR 7 R 8; R 5 - represents NO 2, CN, C (O) R 9, SO 2 R 10 or NR 11 R 12; R7 e. R8 represent, independently of one another, hydrogen or C1 -C6 alkyl; R 9 represents hydrogen, C 1 -C 6 alkylC 1 -C 3 cycloalkyl, C 1 -C 6 alkoxy or NR 7 R 8, R 10 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or NR 7 R 8; R 11 and R 12 are independently hydrogen, C 1 -C 6 -alkyl, SO 2 -C 1 -C 6 -alkyl, or together with the N-atom a 5-membered heteroaryl group optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, or C 3 -C 6 cycloalkyl; R13 is hydroxy, C1-C6 alkyl or C3-C5 cycloalkyl; and the pharmaceutically acceptable acid addition salts thereof, with the proviso that. 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chlorophenyl) piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (4- 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- [3- (trifluoromethyl) phenyl] piperazine, 4- (3-amino-4-nitrophenyl) -1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl-4- (dimethylamino) -2-methoxy- 4-nitrophenyl) piperazine, 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl-1- (4-nitrophenyl) piperazine, 1- (2-chloro-4-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] piperazine, 1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -4- (2,4-dinitrophenyl) -2- (4-chloro-2-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -piperazine 4- [4- (dimethylamino) -2-methoxy-5- 2-methylpiperazine and 1 - [(2-benzyloxy-5-formyl) benzoyl] -4-phenylpiperazine are excluded.

Outro enquadramento da presente invenção são compostos de fórmula IaAnother embodiment of the present invention are compounds of formula Ia

em que R representa hidrogénio ou halogéneo; R' representa hidrogénio ou halogéneo; R" representa CN, C(0)— alquilo Ci-Ce, alquilo Ci~C6 substituído por halogéneo ou Ξ (Ό) 2-alquilo Ci-C6; R"’ representa hidrogénio; 13 R5 representa S (0) 2~ alquilo Οχ-Οε, S(0)2NH2 ou N02; e R2 representa alquilo Cx-Cg, cicloalquilo C3-C6, (alqui Ci~ Οθ)- cicloalquilo C3-C6, alquilo C1-C6 substituído por halogéneo, ^(CH2)20_ alquilo Οχ-Cs, benzilo ou arilo, eventualmente substituído por halogéneo; e os seus sais de adição de ácido aceitáveis sob o ponto de vista farmacêutico,· com a excepção de 1- [5-(amino-sulfonil)-2-metoxibenzoil]-4-(3-clor.ofe-nil) -p.iperazina e ^ jL--[r5- (amino-sulfonil) -2-metoxibenzoil] -4- [3- (trifluoro-metil)fenil]-piperazina.in which R represents hydrogen or halogen; R 'is hydrogen or halogen; R " represents CN, C (O) -C1-6 alkyl, C1-6 alkyl substituted by halogen or Ξ (Ό) 2-C1-6 alkyl; R " 'is hydrogen; R 5 represents S (O) 2 -alkyl χ-ε, S (O) 2 NH 2 or NO 2; and R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1-6 alkyl) - (C 3 -C 6) cycloalkyl, C 1 -C 6 cycloalkyl substituted by halogen, (CH 2) 20, C ??? alkyl, benzyl or aryl, optionally substituted by halogen; and the pharmaceutically acceptable acid addition salts thereof, with the exception of 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chlorophenyl) -p piperazinyl] piperazine and N - [[5- (aminosulfonyl) -2-methoxybenzoyl] -4- [3- (trifluoromethyl) phenyl] piperazine.

Um outro ..enquadramento da presente invenção são os compostos de fórmula geral Ia, em que o símbolo R representa A hidrogénio ou flúor; o símbolo R' representa hidrogénio ou flúor; o símbolo R" representa CN, C(0)CH3, CF3 ou S{0)2_CH3; o símbolo R'" representa hidrogénio; o símbolo R5 representa S(0)2_CH3, S(0)2NH2 ou N02; e o símbolo R2 representa alquilo- (Ci-C6), -CH2-ciclopro-pilo, ciclopentilo, -CH2-CF3 ou - (CH2)2-0-CH3, benzilo ou fenilo substituído por flúor; por exemplo, os seguintes compostos: 2- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona, l-{3-fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzo-il)-piperazin-l-il]-fenil}-etanona, 14 4-[4-(2-isobutoxi-S-metano-sulfonil-benzoil)-pipera-zin-l-il]-benzonitrilo, 3- fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 2-fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, (2-isobutoxi-5-metano-sulfonil-fenil) - [4- (4-trifluoro-metil-fenil)-piperazin-l-il]-metanona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona ou [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona.A further embodiment of the present invention are the compounds of formula Ia, wherein R is A or hydrogen or fluorine; R 'is hydrogen or fluorine; R " represents CN, C (O) CH 3, CF 3 or S (O) 2 CH 3; R '" represents hydrogen; R 5 is S (O) 2 CH 3, S (O) 2 NH 2 or NO 2; and R2 is (C1 -C6) -alkyl, -CH2 -cyclopropyl, cyclopentyl, -CH2 -CF3 or - (CH2) 2 -O-CH3, benzyl or phenyl substituted by fluorine; for example the following compounds: 2-fluoro-4- [4- (2-isopropoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile, [4- (3-fluoro-4- 1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 1- {3-fluoro-4- [4- (2-isobutoxy-5-methano- sulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone, 4- [4- (2-isobutoxy-S-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, Fluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2-fluoro-4- [4- (2-isobutoxy- sulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, (2-isobutoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone or [4- (3-fluoro- phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone.

Um outro enquadramento da presente invenção, são os compostos em que o símbolo R5 representa 8(0)2-0¾ e o símbolo R2 . representa CH'2-ciclopropilo, por exemplo, o seguinte composto: 4- [4- (2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-pi-perazin-l-il]-3-fluoro-benzonitrilo. .A further embodiment of the present invention are those compounds wherein R 5 is 8 (O) 2-O, and R 2 is. represents CH 2 -cyclopropyl, for example, the following compound: 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile. .

Os compostos de fórmula geral Ia são ainda aqueles em que o símbolo R5 representa S (0)2-0¾ e o símbolo R2 representa CH2CF3, por exemplo, os seguintes compostos: [4-(2—fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil.-2- {2,2,2-trifluoro-etoxi) -fenil] -etanona ou [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-etanona.The compounds of formula Ia are further those wherein R 5 is S (O) 2 -O 2 and R 2 is CH 2 CF 3, for example the following compounds: [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -ethanone or [4- (3-fluoro-4-trifluoromethyl-phenyl) - piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -ethanone.

Os compostos de fórmula geral Ia são ainda aqueles em que o símbolo R5 representa S(0)2-CH3 e o símbolo R2 15 representa ciclopentilo, por exemplo, os seguintes compostos: 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pipe-razin-l-il]-3-fluoro-benzonitrilo ou ' 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pipe-razin-l-il]-2-fluoro-benzonitrilo.The compounds of formula Ia are further those wherein R 5 is S (O) 2 -CH 3 and R 15 is cyclopentyl, for example the following compounds: 4- [4- (2-cyclopentyloxy-5-methane benzenesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile or 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin- 2-fluoro-benzonitrile.

Os compostos de fórmula geral I da presente- invenção preferidos são aqueles em que o símbolo Ar representa fenilo substituído, o símbolo R2 representa alquilo-(Ci-Cg) e o símbolo R5 representa 3(0)20¾ ou S(0)2CH2CH3. Estão neste grupo os compostos específicos que se seguem: . 1-{3-fluoro-4- [4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, 3- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitril.o, 2- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben- zoil)-piperazin-l-il]-benzonítrilo, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-{2-isopropoxi-5-metano-sulfonil-fenil)-metanona, 1- {3-fluoro-4-[4-{2-isobutoxi-5-metano-sulfonil-benzo-i!)-piperazin-l-il]-fenil}-etanona, 4- [4-(2-isobutoxi-5-metano-sulfonil-benzoil)-pipera-zin-l-ii]-benzonítrilo, 3- fluoro-4- [4- (2-isobutoxi-5-metano-sulfoni.l-benzoil) -piperazin^l-il]-benzonítrilo,· 2- fluoro-4- [4- (2-isobutoxi-5-metano-s.ulfonil-benzoil) -piperazin-l-il]-benzonítrilo, (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metíl-feníl}-píperazín-l-íl]-metanona, 16 [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona, [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona, [4- (2-fluoro-4-nietano-sulfonil-fenil) -piperazin-l-il]-2-isobutoxi-5-metano-sulfonil-fenil)-metanona, [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-2-isopropoxi-5-metano-sulfonil-fenil)-metanona, 2.3- difluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 2.3- difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 2.5- difluoro-4-[4-(2-isobutóxi-5-metano-sulfonil-ben-zoil.) -piperazin-l-il] -benzonitrilo, 2.6- difluoro-4- [4-(2-isobutoxi-5-metano-sulfonil-ben-zoíl)-piperazin-l-il]-benzonitrilo, 3,5-difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 4-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -2,3-difluoro-benzonitrilo, 4-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-pipera-zin-l-il]-3-difluoro-benzonitrilo, (2-terc-butoxi-5-metano-s.ulfonil-fenil) - [4- (2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(2,5-diflu-oro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona, 1-(4-{4-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}-3-fluoro-fenil)-etanona, 4—{4—[2—(2,2-dimetil-propoxi)-5-metano-sulfonil-benzo-il]-piperazin-l-il}-benzonitrilo, 4 — {4 —[2-(2,2-dimetil-propoxi)-5-metano-sulfonil^benzo-il]-piperazin-l-il}-3-fluoro-benzonitrilo, 17 4-{ 4- [2- (2,2-dimetil-propoxi) -5-metano-sulfonil-benzo-il]-piperazin-l-il}-2-fluoro-benzonitrilo, [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluorometil-fenil)-piperazin-1-il] -metanona, [2- (2,2-dimetil-propoxi) -5-metano-sulfonil-fen.il] - [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-{2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(2-fluoro-4-etano-sulfonil-fenil)-piperazin-l-il]-metanona, rac-l-{4-[4-(2-sec-butoxi-5-metano-sulfonil-benzoil)- . piperazin-l-il]-3-fluorofenil}-etanona, rac-4-[4-(2-sec-butoxi-5-metano-sulfonil-benzoil)-pi-perazin-l-il]-3-fluoro-benzonitrilo, rac-4-[4- (2-sec-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-f luoro-benzoni trilo, rac-(2-sec-butoxi-5-metano-sulfonil-fenil)-[4-(2-fluo-ro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, rac-(2-sec-butoxi-5-metano-sulfonil-fenil)-[4-(3-fluo-ro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-ί3ορΓοροχί-5-π^3Γΐθ-3'α1£οηί1-ίθηί1) - [4- (4-trifluo-· rometano-sulfonil-fenil)-piperazin-l-il]-metanona, (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metano-sulfonil-fenil)-piperazin-l-il]-metanona, 2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-pipera-zin-l-il]-5-trifluorometil-benzonitrilo, l-{2-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, [4-(3-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona, 18 1- {2-2-fluoro-4-ί4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, 2- [4- (2-isobutoxi-5-metano-sulfonil-benzoil) -pipera-zin-l-il]-5-trifluorometil-benzonitrilo, (5-etano-sulfonil-2-isopropoxi-fenil) - [4- (2-fluoro-4-trifluorometil-fenil)piperazin-l-il]-metanona, [4-(4-difluorometil-2-fluoro-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona, [4-{3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -(2-isopropoxi-5-^metano-sulfonil-fenil)-metanona, 3- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzaldeído, [4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-(2-Í5obiitoxi-5-metano-sulfonil-fenil) -metanona, rac-{2-sec-butoxi-5-metano-sulfonil-fenil)-[4-(4-eta-no-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, [4-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazin-l-il]·- (2-isopropoxi-5-metano-sulfonil-fenil)-metanona, [4-(4-ciclopentano-sulfonil-2-fluoro-fenil)-piperazin-l-il] - (2-isopropoxi-5-metana-sulfonil-fenil) -metanona, [4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-: 1-il] - (2-isobutox.i-5-metano-sulfonil-fenil) -metanona, e [4-(4-ciclopropano-sulfonil-2,5-difluoro-fenil)-pipe-razin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona.Preferred compounds of the present invention are those wherein Ar is substituted phenyl, R 2 is C 1 -C 6 -alkyl and R 5 is 3 (O) 20, or S (O) 2 CH 2 CH 3. In this group are the following specific compounds:. 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone, 3-fluoro-4- [4- 2-isopropoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile, 2-fluoro-4- [4- (2-isopropoxy-5-methanesulfonylbenzoyl) 4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 1- 4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone, 4- [4- (2-isobutoxy-5- 1-yl] -benzonitrile, 3-fluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -piperazin- -benzonitrile, 2-fluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, (2-isobutoxy-5-methanesulfonyl-phenyl) ) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-fluoro-4-trifluoromethyl-phenyl) -piperazin- isobutoxy-5-methanesulfonyl-phenyl) -methanone, [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5- phenyl) -piperazin-1-yl] -2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, [4- (2-fluoro-4-methanesulfonyl- 2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 2,3-difluoro-4- [4- (2-isopropoxy-5- 2,3-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -piperazin-1-yl] -benzonitrile, benzonitrile, 2,5-difluoro-4- [4- (2-isobutoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile, 2,6-difluoro-4- [4- (2- isobutoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile, 3,5-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile, 4- [4- 2-tert-butoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -3-difluorobenzonitrile, (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- - (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-tert-butoxy-5-methano-su (4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone, 1- (4- {4- [2- (2,2- dimethylpropoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -3-fluoro-phenyl) -ethanone, 4- {4- [2- (2,2-dimethyl-propoxy) -5- benzenesulfonyl] -piperazin-1-yl} -benzonitrile, 4- {4- [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl] -benzoyl] -piperazin- yl} -3-fluoro-benzonitrile, 17 4- {4- [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -2- fluoro-benzonitrile, [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- 2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- { Dimethylpropoxy) -5-methanesulfonyl-phenyl] - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- (2,2- propoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-ethanesulfonyl-phenyl) -piperazin-1-yl] -methanone, rac-1- {4- [4- butoxy-5-methanesulfonyl-benzoyl) -. piperazin-1-yl] -3-fluorophenyl} ethanone, rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3- benzonitrile, rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile, rac- (2-sec-butoxy-5- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, rac- (2-sec-butoxy-5-methanesulfonyl-phenyl) ) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-pyrrolidin-5-yl) -3,4-a] - (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone, (2-isobutoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethanesulfonyl-phenyl ) -piperazin-1-yl] -methanone, 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5-trifluoromethyl-benzonitrile, 1- {2- fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone, [4- (3-fluoro-4-methanesulfonyl-phenyl ) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, 1- {2-2-fluoro-4- [4- (2-isobutoxy-5- ethanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone, 2- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5- 4-trifluoromethyl-benzonitrile, (5-ethanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [4- (4-difluoromethyl- 2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin- yl] -benzaldehyde, [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2- (5-methoxy-5-methanesulfonyl-phenyl) -methanone, rac- { 2-sec-butoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, [4- (4-cyclobutane 2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, [4- (4-cyclopentanesulfonyl- -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, [4- (4-cyclop 2-fluoro-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, and [4- (4-cyclopropanesulfonyl- 5-difluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone.

Ainda um grupo de compostos de fórmula geral I preferido, tem a ver com aqueles em que o simbolo Ar representa fenilo substituído, o símbolo R2 representa (CH2) n~ciclo-alquilo-(C3-C7) e o símbolo R5 representa .S(0)2CH3, .por exemplo, os seguintes compostos: 19 1-{4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-3-fluoro-fenil}-etanona, 4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-' piperazin-l-il]-benzonitrilo, 4-[4- (2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo, 4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]^2-fluoro-benzonitrilo, {2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, {2-ciclopropilmetoxi-5-metano-sulfonil-fenil}-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, 1—{4—[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pi-perazin-l-il]-3-fluoro-fenil}-etanona, 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo', 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -3-f luoro-benzonitrilo, 4- [4- (2-ciclopentiloxi-5-metano-sulfonil-berLzoil) -pi-perazin-l-il] -2-fluoro-benzonitrilo, (2-ciclopentiloxi-5-metano-su.lfonil-fenil) - [4- (2-fluo-ro-4-trifluo.rometil-fenil)-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(3-fluo-ro-4-trifluorometil-fenil}-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-{4-tri-fluorometil-fenil)-piperazin-l-il]-metanona,. rac-[2-(1-ciclopropil-etoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, 20 4- [4- (2-ciclopentiloxi-5-rr\etano-sulfonil-benzoil) -pi perazin-l-il]-2,3-difluoro-benzonitrilo, 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pi perazin-l-il]-2,5-difluoro-benzonitrilo, 4-[4-(2-ciclobutilmetòxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 4-[4-(2-ciclobutilmetoxi“5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo, 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo, (2-ciclobutilmetoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il] -metanona, 1 — {4 —[4-(2-ciclobutilmetoxi-5~metano-sulfonil-ben-zoíl)-piperazin-l-il]-3-fluoro-fenil}-etanona, 2-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-5-trifluorometil-benzonitrilo, 4- [4- (2-ci'clobutilmetoxi-5-metano-sulfonil-benzoil) -piperazin-l-il]-2,3-difluoro-benzonitrilo, 4-[4-{2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,5-difluoro-benzonitrilo, 4-[4-{2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3,5-difluoro-benzonitrilo, 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,6-difluoro-benzonitrilo, 4-[4-{2-ciclopropilmetoxi-5-metano-sulfonil-benzoil) piperazin-l-il]-3,5-difluoro-benzonitrilo, 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pi perazin-l-il]-3,5-difluoro-benzonitrilo, 4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil) piperazin-l-il]-2,6-difluoro-benzonitrilo, 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-pi perazin-l-il]-2,6-difluoro-benzonitrilo, 5-cloro-2-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 4-[4-(2-ciclo-hexiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -benzonitrilo, 4-[4-(2-ciclo-hexiloxi-5-métano-sulfonil-benzoil)-piperazin-l-il] -3-fluoro-benzonitrilo,' 4- [4- (2-ciclo-hexiloxi-5-me'tano-sulfonil-benzoil) -piperazin-l-il] -2-fluoro-benzonitrilo,. (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-(4-tri-fluorometil-fenil)-piperazin-l-il]-metanona, {2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-(3-fluo-ro-4-trifluorométil-fenil)-piperazin-l-il]-metanona, (2-ciclo-hexiloxi-5-metano-sulfonil-fenil). - [4- (2-fluo-ro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona, 1—{4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzõil)-pi-perazin-l-íl]-3-fluoro-fenil}-etanona, 4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -3-fluoro-benzonitrilo, (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(3-fluoro-4-tri.f luorometil-fenil) -piperazin-l-il) -metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil·) - [4- (4-tri-fluorometano-sulfonil-fenil)-piperazin-l-il]-metanona, 1- {4- [4-(2-ciclopropilmetoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-2-fluoro-fenil}-etanona, 2- [4-(2-ciclopentiloxí-5-metano-sulfoníl-benzoil)-pi-perazin-l-il]-5-trifluorometil-benzonitrilo, (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(4-eta-no-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-(4-eta-no-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, 22 (2-ciclopentiloxi-5-metano-sulfonil-fen.il) - [4- (4-ci-cló-propano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-(4-ci-clo-propano-sulfonil-2-fluoro-fenil)-piperazin-l-il]- metanona, (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(4-ciclo-propano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, São ainda preferidos os compostos, em que o símbolo Ar representa fenild substituído, o símbolo· R2 representa alquilo-(Ci-C6) substituído por halogéneo e o símbolo R5 representa 3(0)20¾. Os compostos que seguem pertencem a este.grupo: 1-(3—fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-etoxi)-benzoil]-piperazin-l-il}-fenil)-etanona, 3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, [4-{2—fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona, [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxí)-fenil]-metanona, [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-ilj-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona, 3-fluoro-4-{ 4-[5-metano-sulfonil--2-(3, 3, 3-trifluoro-propoxí)-benzoil]-piperazin-l-il}-benzonitrilo, 23 [4- (3-fluoro-4-trifluorometil-fenil) -piperazin-l-il] -[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-fenil]-metanona, [4-(2—fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-fenil]-metanona, 1- (3-fluoro-4-{4-[5-metano-sulfonil-2-(3,3,3-trifluo-ro-propoxi)-benzoil]-piperazin-l-il}-fenil)-etanona, 2.5- difluoro-4-[4-(5-metano-sulfonil-2-trifluorome-toxi-benzoil)-piperazin-l-il]-benzonitrilo, 2.3- difluoro-4-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}-bênzonitrilo, 2- fluoro-4-(4-[5-metano-sulfonil-2-(2,2,3,3,3-penta- fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, (5-metano-sulfonil-2-(2,2,3,3,3-pentàfluoro-propoxi)- fe-nil] -[4-(4-trifluorometilfenil)-piperazin-l-il]-metanona, 2.3- difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-pen-ta-fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 3.5- difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-pen-ta^-f luoro-propoxi) -benzoil] -piperazin-l-il} -benzonitrilo, 2-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfo-nil-benzoil]-piperazin-l-il}-5-trifluoròmetil-benzoni-trilo, rac-2,3-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 2- fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetrafluo-ro-propoxi)-benzoil]-piperazin-l-il]-benzonitrilo, 3- fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-l-il]-benzonitrilo, 24 [5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi!)-fe-nil]-[4-(4-trifluorometilfenil)-piperazin-l-il]-me tanona, [4- (2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-fe-nil] -metanona, 2,3-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 3,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, [4-(3,4-dicloro-fenil)-piperazin-l-il]-[5-metano-sul-fonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona, rac-5-cloro-2-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzoni- · trilo, rac-3,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, rac-2,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, rac-2,6-dífluoro-4-{4-[S-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, rac-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-me-til-etoxi) -benzoil] -piperazin-1-i.l}-benzonitrilo, rac-3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-l-metil-etoxi)-benzoil)-piperazin-l-il}-benzonitrilo, rac-2-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-l-metíl-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 25 rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fen.il] - [4- (4-trifluorometil-fenil) -piperazin-1-il]-metanona, rac-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-1-il]-[ 5-metano-sulfonil-2-(2,2,2-trifluoro-l-metiÍ-eto-xi)-fenil]-metanona, rac-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-eto-xi)-fenil]-metanona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-((S ou R)-2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona, [5-metano-sulfonil-2-( (S ou R)-2,2,2-trifluoro-l-me-til-etoxi) -fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona. e - [5-metano-sulfonil-2-( (R ou S) -2,2,2-trifluoro-l-me-til-etoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona. Òs compostos de fórmula geral I da presente invenção preferidos são aqueles· .em que o símbolo Ar representa fenilo substituído, o símbolo R1 2 3 4 representa alquilo-(Ci-Cg) , alquilo-(Ci-C6) substituído por halogéneo, {CH2·) n-cicloal-quilo- (C3-C7} , biciclo [2.2.1] heptilo, (CH2) n-0-alquilo- (Ci~ Cg) ou (CH2) n“heterocicloalquilo e o símbolo R5 representa N02a por exemplo, os compostos seguintes: 26 1 (3-fluoro-4-{4-[2-(2-metoxi-etoxi)-5-nitro-benzoil]-piperazin-l-il}-fenil)-etanona, 2 (2-isopropoxi-5-nitro-fenil)-[4-(4-trifluorometil-fe- 3 nil)-piperazin-l-il]-metanona, 4 (2-ciclopropilmetoxi-5-nitro-fenil)-[4-(4-trifluorome 5 til-fenil} -piperazin-l-il]-metanona, (2-ciclobutilmetoxi-5-nitro-fenil)-[4-(4-trifluorome-til-fenil)-piperazin-l-il]-metanona, (2-butoxi-5-nitro-fenil) - [4-(4-^trifluorometil-fenil) -piperazin-l-il]-metanona, [2-(2,2-dimetil-propoxi)-5-nitro-fenil]-[4-(4-trifluo-rometil-fenil)-piperazin-l-il]-metanona, (2-isobutoxi-5-nitro-fenil)-[4-(4-trifluorometil-fe-nil)-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, (5-nitro-2-propoxi-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-ciclobutoxi-5-nitro-fenil)-[4-(4-trifluorometil-fè-nil)-piperazin-l-il]-metanona, rac-(2-sec-butoxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il] -metanona, [5-nitro-2-(2,2,3,3-tetrafluoro-propoxi)-fenil]—[4—(4— trifluorometil-fenil)-piperazin-l-il]-metanona, [5-nitro-2-(2,2,2-triflqoro-etoxi)-fenil]-[4-(4-trifluorometil-fenil) -piperazin-l-il]-metanona, [2-(biciclo[2,2,1]-hept-2-iloxi)-5-nitro-fenil]-(4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-(2-cloro-etoxi)-5-nitro-fenil]-[4-(4-trifluoro-metil-fenil)-piperazin-l-il]-metanona e [5-nitro-2-(2,2,3,3,3-pentafluoro-propoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona. São ainda compostos preferidos, de fórmula I,. aqueles em que o símbolo Ar representa fenilo substituído, o símbolo R2 representa alquilo- (Ci-C6) , alquilo-(Ci-C6) substituído por halogéneo ou (CH2) n-cicloalquilo- (C3-C7) e o símbolo R5 representa S(0)2NHCH3. 27 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]-N-metil-4-trifluorometoxi-benzeno-sulfonamida, 3- [4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]- 4- isobutoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclopentiloxi-N-metil-benzeno-sulfonamida, 3- [4- (4-ciano-3-fluoro-f'enil) -piperazino-l-carbonil] - 4- ciclobutoxi-N-metil-benzeno-sulfonamida, [4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]-4-ciclobutilmetoxi-N-metil-benzeno-sulfonamida, 3- [4- (4-ciano-fenil) -piperazino-l-carbonil]'-4-isobu-toxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-ciclo-pentiloxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-cíclobu-tilmetoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- isobutoxi-N-metil-benzeno-sulfonaraida, 3- [4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- (2,2-dimetil-propõxi)-N-metil-benzeno-sulfonamida, 3— E 4 —(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- isopropoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-çiano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclopentiloxi-N-metil-benzeno-sulfonamida, 3- [4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclobutoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- . 4- ciclopropilinetoxi-N-metil-benzeno-sulfonaniida, 3- [4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclobutilmetoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazino-l-carbonil]- 4- isobutoxi-N-metil-benzeno-sulfonamida, 28 3- [4-(4-acetil-2-fluoro-fenil)-piperazino-l-carbonil]- 4- {2,2-dimetil-propoxi)-N-metil-benzeno-sulfonamida,. 3- [4-(4-acetil~2-fluoro-fenil)^piperazino-l-carbonil]- 4- ciclopentiloxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclobutoxi-N-metil-benzeno-sulfonamida, 3- [4- (4-acetil-2-fluoro-fenil)-piperazino-l-carbonil]- 4- ciclopropilmetoxi-N-metil-benzeno-sulfonamida, 4-isobutoxi-N-metil-3-[4-(4-trifluororaetil-fenil)-pi-perazino-l-carbonil]-benzeno-sulfonamida, 4-(2,2-dimetil-propoxi)-N-metil-3-[4-(4-trifluorome-til-fenil)-piperazino-l-carbonil]-benzeno-sulfonamida, 4-isopropoxi-N-metil-3-[4-(4-trifluorometil-fenil)-pl-perazino-l-carbonil]-benzeno-sulfonamida, 4-ciclopentiloxi-N-metil-3-[4-(4-trifluorometÍl-fe-' nil) -piperazino-l-carbonil] -benzeno-sulfonamida,· 4-ciclobutoxi-N-metil-3- [ 4- (4-trifluòrome.til-fenil) -piperazino-l-carbonil]-benzeno-sulfonamida, 4-ciclopropilmetoxi-N-metil-3-[4-(4-trifluorometil-fe-nil)-piperazino-l-carbonil]-benzeno-sulfonamida, 4-ciclobutilmetoxi-N-metil-3-[4-(4-trifluorometil-fe-nil)-piperazino-l-carbonil]-benzeno-sulfonamida, N-metil-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil] -4-(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]-N-metil-4-(2,2,2-trifluoro-etoxi)-benzeno-sulfonamida, N-metil-4-(2,2,2-trifluoro-etoxi)-3-[4-(4-trifluorome-til-fenil)-pipèrazino-l-carbonil]-benzeno-sulfonamida, rac-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi)-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzeno-sulfonamida, 29 rac-3-[4-(4-ciano-2,5-difluoro-fenil)-piperazino-1-carbonil]-N-metil-4-{2,2, 2-trifluoro-l-metil-etoxi)-ben-zeno-sulfonamida e rac-3-[4-(4-ciano-2,3-difluoro-fenil)-piperazino-l-carbonil]-N-raetil-4-(2,2,2-trifluoro-l-metil-etoxi)-benzeno-sulfonamida.A further preferred group of compounds of Formula I is those in which Ar is substituted phenyl, R2 is (CH2) n-cyclo- (C3-C7) -cycloalkyl and R5 is .S (0) 2 CH 3, for example the following compounds: 1- {4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl } -ethanone, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl ) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2- 4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl} - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin- 1-yl] -methanone, 1- {4- [4- (2-cyclopentyloxy-5-methanesulfonyl- benzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone, 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile ' , 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclopentyloxy-5-methanesulfonyl- 2-fluoro-benzonitrile, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl- phenyl) -piperazin-1-yl] -methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone. rac- [2- (1-cyclopropyl-ethoxy) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 4- [4- (2- 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile, 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -pi [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (2-pyridyl) 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile, 4- [4- (2-cyclobutylmethoxy-5- -3-fluoro-benzonitrile, (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- 2-cyclobutylmethoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone, 2- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) - piperazin-1-yl] -5-trifluoromethyl-benzonitrile, 4- [4- (2-Cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile, 4 - [4- (2-cyclobutylmethoxy- 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,5-difluorobenzonitrile, 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] - 3,5-difluoro-benzonitrile, 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile, 4- [4- {2- cyclopropylmethoxy-5-methanesulfonylbenzoyl) piperazin-1-yl] -3,5-difluorobenzonitrile, 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl ] -3,5-difluorobenzonitrile, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonylbenzoyl) piperazin-1-yl] -2,6-difluoro-benzonitrile, 4- [4- (2- 5-chloro-2- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluorobenzonitrile, piperazin-1-yl] -benzonitrile, 4- [4- (2-cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (2- hexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin- yl] -2-fluoro-benzonitrile. (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, {2-cyclohexyloxy-5-methanesulfonyl -phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy-5-methanesulfonyl-phenyl). - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- (2-cyclobutoxy-5-methanesulfonyl-benzyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone, 4- [4- (2-cyclobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile , (2-cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl) -methanone, (2-cyclopentyloxy-5-methane (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl- benzoyl) -piperazin-1-yl] -2-fluoro-phenyl} -ethanone, 2- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5- (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclopropylmethoxy- 5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy- phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (4-cylo-propanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy- -5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclobutoxy-5-methanesulfonyl- -phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone. Further preferred are the compounds, wherein Ar is substituted phenyl, the symbol R2 represents halogen-substituted (C1-C6) alkyl and R5 represents 3 (O) 20¾. The following compounds belong to this group: 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin- 1-yl} -phenyl) -ethanone, 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin- benzonitrile, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone, [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone, - (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone, 3-fluoro -4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 23 [4- (3-fluoro-4- trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -phenyl] -methanone, [4- (2-fluoro-4-trifluoromethyl -phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -phenyl] -methanone, 1- (3-fluoro-4- {4- [ 5-methanesulfonyl-2- (3,3,3-trifluoromethyl- o-ro-propoxy) -benzoyl] -piperazin-1-yl} -phenyl) -ethanone, 2,5-difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1 -yl] -benzonitrile, 2,3-difluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile, 2- fluoro-4- (4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, (5-methane 2- (2,2,3,3,3-pentafluoro-propoxy) -phenyl] - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone, 2,3-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-penta-fluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 2- {4- - [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -5-trifluoromethyl-benzonitrile, rac-2,3-difluoro- 4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 2-fluoro- {4- [5-methanesulfonyl-2- (2,2,3,3-tetr benzyl] -piperazin-1-yl] -benzonitrile, 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro- propoxy) -benzoyl] -piperazin-1-yl] -benzonitrile, [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl- 3,3-tetrafluoro-propoxy) -phenyl] -methanone, 2,3-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy ) -benzoyl] -piperazin-1-yl} -benzonitrile, 3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) benzoyl] -piperazin-1-yl} -benzonitrile, [4- (3,4-dichloro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-ethoxy) -phenyl] -methanone, rac-5-chloro-2- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro- ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-2,5-difluoro-4- {4- [5-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-2,6-difluoro-4- {4- [S-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac 4- {4- [5-methanesulfonyl- 2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-3-fluoro-4- {4- [5-methanesulfonyl- 2-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-benzoyl) -piperazin-1-yl} -benzonitrile, 2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy ) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, rac- [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, rac- [4- (3-fluoro-4-trifluoromethyl-phenyl) - piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, [4- (2-fluoro-4-trifluoromethyl -phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro-1 ethoxy) -phenyl] -methanone, [5-methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- - (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone. and - [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazine yl] -methanone. Preferred compounds of formula I of the present invention are those wherein Ar is substituted phenyl, R1 is NH- (C1 -C6) -alkyl, (C1 -C6) -alkyl substituted with halogen, CH 2 -) n-cycloalkyl- (C 3 -C 7) bicyclo [2.2.1] heptyl, (CH 2) n -O- (C 1 -C 6) -alkyl or (CH 2) n -heterocycloalkyl and R 5 represents NO 2 a for example, the following compounds: 1- (3-fluoro-4- {4- [2- (2-methoxy-ethoxy) -5-nitro-benzoyl] -piperazin-1-yl} -phenyl) -ethanone, 2 (2-isopropoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 4- (2-cyclopropylmethoxy-5-nitro-phenyl) - [4- - (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclobutylmethoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -methanone, [2- (2,2-dimethyl-propoxy) -piperazin-1-yl] -methanone, [2- (4-trifluoromethyl-phenyl) -piperazin- 5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-isobutoxy-5-nitro-phenyl) - [4- (4- 1-yl] -methanone, (2-cyclopentyloxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclobutoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl- 1-yl] -methanone, rac- (2-sec-butoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin- [5-nitro-2- (2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [5-nitro-2- - [2,2,2-trifluoro-ethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- (bicyclo [2.2.1] hept -2-yloxy) -5-nitro-phenyl] - (4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- (2-chloroethoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone and [5-nitro-2- (2,2,3,3,3-pentafluoro-propoxy) -phenyl] - [ 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone. Further preferred compounds of formula I are preferred. those in which Ar is phenyl substituted, R2 is (C1 -C6) -alkyl, (C1 -C6) -alkyl substituted by halogen or (CH2) n-C3 -C7 -cycloalkyl and R5 represents S (O) 2 NHCH 3. 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4-trifluoromethoxy-benzenesulfonamide, 3- [4- (4-cyano-3-fluoro phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy N-methylbenzenesulfonamide, 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide, [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-phenyl) -piperazine- -4-isobutyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) 1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2,2- -dimethyl-propoxy) -N-methyl-benzenesulfonamide, 3-E4 - ( 4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-N-methyl-benzenesulfonamide, 3- [4- (4-Amino-2-fluoro-phenyl) -piperazin-1 carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl- sulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -. Cyclobutylmethoxy-N-methylbenzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide, 3-3- [4- (4-Acetyl-2-fluoro-phenyl) ) -piperazine-1-carbonyl] -4- (2,2-dimethyl-propoxy) -N-methyl-benzenesulfonamide. 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-acetyl- phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopropylmethoxy- N-methyl-benzenesulfonamide, 4-isobutoxy-N-methyl-3- [4- (4-trifluorouraethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4- (2,2- -propoxy) -N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4-isopropoxy-N-methyl-3- [4- (4- trifluoromethyl-phenyl) -pentazino-1-carbonyl] -benzenesulfonamide, 4-cyclopentyloxy-N-methyl-3- [4- (4-trifluoromethylphenyl) -piperazine-1-carbonyl] -benzene 4-cyclopropylmethoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, - (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4-cyclobutylmethoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl ] -benzenesulfonamide, N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide, N-methyl- (2,2,2-trifluoro-ethoxy) -3- [4- (4-trifluoromethyl-phenyl) -piperrazine-1-carbonyl] -benzenesulfonamide, rac-N-methyl-4- , 2-trifluoro-1-methyl-ethoxy) -3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, rac-3- [4- (4-cyano-2- , 5-difluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide and rac 3- [4- (4-cyano-2,3-difluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide.

Um outro grupo de compostos de fórmula geral I preferidos,. é aquele em que o símbolo Ar representa um grupo heteroarilo, com 6 átomos no núcleo, substituído, contendo um, dois ou três átomos de azoto, o símbolo R2 representa alquilo- (Ci-C6) ou (0¾) n_cicloalquilo- (C3-C7) e o símbolo R5 representa SO2CH3, por exemplo: [4-(3-cloro-S-trifluorometil-piridin-2-il)-piperazin-1-il)-(2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-metanona, 6-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-nicotinonitrilo, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(5-tri-. fluorometil-piridin-2-il)-^piperazin-l-il]-metanona, [4-(3-cloro-5-trifluorometil-piridin-2-il) -piperazin-. 1-il]-(2-ciclopentiloxi-5-metano-sulfonil-fenil)-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(6-tri-fluorometil-piridin-3-il)-piperazin-l-il]-metanona, [4-(3-fluoro-5~trifluorometil-piridin-2-il)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil)-metanona e (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(3-. fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona. 30 São ainda preferidos os compostos de fórmula geral I, em que o símbolo Ar representa um grupo heteroarilo, com 6 átomos no núcleo, substituído, contendo um, dois ou três átomos de azoto, o símbolo R2 representa alquilo-(Ci-Cô) substituído por halogéneo e o símbolo R5 representa SÒ2CH3, por exemplo, os compostos seguintes: rac-[4-(3-cloro-5-trifluorometil-piridin-2-il)-pipera-zin-l-il]-[5-metano“Sulfonil-2-(2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona, rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-eto-xi)-fenil]-[4-(5-trifluorometil-piridin-2-il)-pipera-zin-l-il]-metanona, rac-[4-(5-bromo-piridin-2-il)-piperazin-l-il]-[5-meta-no-sulfonil-2- (2,2,2-trifluoro-l-metil-etoxi) -fenil] metanona, rac-[4-(3-fluoro-5-trifluorometil-piridin-2-il)-pipe-razin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi )-fenil]-metanona, rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-eto-. xí)-fenil]-[4-(6-trifluorometil-piridin-2-il)-piperazin-l-il] -metanona, [5-metano-sulfonil-2-((S òu R)-2,2,2-trifluoro-l-metil-etoxi) -fenil]-[4-(5-trifluorometil-piridin-2-il)-pipera-zin-l-il]-metanona, [5-metano-sulfonil-2-( (R ou S)-2,2,2-trifluoro-l-metil-etoxi) -fenil]-[4-(5-trifluorometil-piridin-2-il)- pipera-zin-l-il]-metanona, [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -[5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-metil-etoxi) -fenil] -metanona e [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperâzin-1—i1]-[5-metano-sulfonil-2-(2,2,2-trifluoro-1,1-dime-til-etoxi)-fenil]-metanona. 31Another preferred group of compounds of formula I. is wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1 -C6) -alkyl or (O) n (C3 -C10) cycloalkyl, C7 alkyl) and R5 is SO2 CH3, for example: [4- (3-chloro-S-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl) - (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) ) -methanone, 6- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -nicotinonitrile, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- 5-trifluoromethyl-pyridin-2-yl) piperazin-1-yl] -methanone, [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-. 1-yl] - (2-cyclopentyloxy-5-methanesulfonyl-phenyl) -methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyridin-3-yl ) -piperazin-1-yl] -methanone, [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) methanone and (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone. Further preferred are the compounds of formula I, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1 -C6) substituted by halogen and R 5 represents S 2 CH 3, for example the following compounds: rac- [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5- methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, rac- [5-methanesulfonyl-2- (2,2,2- methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone, rac- [4- (5-bromo-pyridin-2 1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] methanone, rac- [4- (3- fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - methanone, rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridin-2-yl) - piperazin-1-yl] -methanone, [5-methano- sulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin- yl] -methanone, [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyridin-2 pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2-methyl-piperazin-1-yl] -methanone, [4- (3-fluoro-5-trifluoromethyl- (S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin- - [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] -methanone. 31

Os compostos de fórmula geral I da presente invenção e os seus sais aceitáveis sob o ponto de vista farmacêutico, podem ser preparados por processos conhecidos na. técnica, por.exemplo, pelos processos descritos a seguir, processos que compreendem a) a reacção de um composto de fórmula geralThe compounds of formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by procedures known in the art. For example, by the processes described below, processes comprising a) reacting a compound of general formula

OO

Ar'"Ar '"

II com um composto de fórmula geralII with a compound of general formula

na presença de um agente de activação, tal como, TBTU (2-(lH-benzotríazole-l-il)-1,1,3,3-tetrametiluróniote-trafluoroborato) para se obter um composto de fórmula geralin the presence of an activating agent, such as, TBTU (2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate) to provide a compound of general formula

com os substituintes já definidos antes ou b) a reacção de um composto de fórmula geralwith the substituents already defined above, or b) reacting a compound of formula

3232

V com um composto de fórmula geralV with a compound of general formula

R2OH eventualmente na presença de um catalisador, tal como, Cu (II) e uma base como carbonato de potássio, carbonato de césio ou sódio, para se obter um composto de fórmula geralR 2 OH optionally in the presence of a catalyst such as Cu (II) and a base such as potassium carbonate, cesium or sodium carbonate, to give a compound of general formula

em que o símbolo X representa halogéneo e os outros substituintes. têm os significados definidos antes ou c) a reacçao de um composto de fórmula geralwherein X is halogen and the other substituents. are as defined above, or c) reacting a compound of formula

O OHOH

VI com um composto de fórmula geralVI with a compound of general formula

R2X na presença de uma base e, eventualmente, na' presença de micro-ondas para se.obter um composto de fórmula geral 33R2X in the presence of a base and optionally in the presence of microwaves to obtain a compound of formula 33

d) em que o símbolo X representa halogéneo, mesilato ou triflato e os outros substituintes têm os significados ou composto de ! fórmula < 0 OH r/ AT' T R6- Vv l I-.1 R5 R VI de fórmula geral r2oh nas condições de Mitsunobu na presença de uma fosfina, para se obter um composto de fórmula gerald) wherein X is halogen, mesylate or triflate and the other substituents have the meanings or compound of! formula < In the presence of a phosphine in the presence of a phosphine, to give a compound of general formula

em que os substituintes têm os significados definidos antes ou e) a reacção de um composto de fórmula geralwherein the substituents are as defined above or e) reacting a compound of formula

3434

VIII com um composto de fórmula geralVIII with a compound of general formula

ÃrX para se obter um composto de fórmula geralX to give a compound of formula

em que o símbolo X representa halogéneo e os outros substituintes têm os significados definidos antes ou f) a reacção de um composto de fórmula geralwherein X is halogen and the other substituents are as defined above or f) reacting a compound of formula

R3 R4 la com uma amina ou álcool correspondentes, na presença de um agente de activação, para se obter um composto de fórmula geral ' ;R 3 R 4a with a corresponding amine or alcohol, in the presence of an activating agent, to give a compound of formula ';

em que o símbolo R9 representa alquilo- (Ci~Ce) , cicloalquilo-(C3-C6) , alcoxi-(Ci-Cg) ou NR7R8; e os outros substituintes têm os significados definidos antes ou 35 g) a reacção de um composto de fórmula geralwherein R9 is (C1 -C6) -alkyl, (C3-C6) -cycloalkyl, (C1 -C6) -alkoxy or NR7 R8; and the other substituents are as defined above or 35 g) reacting a compound of formula

íc com um composto de fórmula geral RONH2 para se obter um composto de fórmula geralwith a compound of formula RONH2 to give a compound of general formula

id em que o simbolo R representa H ou alquilo e os outros substituintes têm os significados definidos antes ou h) a reacção de um composto de fórmula geralid wherein R is H or alkyl and the other substituents are as defined above or h) reacting a compound of formula

O OO O

1c com um agente de redução, tal como, boro-hidreto de sódio (quando R representa H) o.u com um agente de alquilação como alquil-lítio (quando R representa alquilo), para se obter um composto de fórmula géral·1c with a reducing agent, such as sodium borohydride (when R representa is H) or with an alkylating agent such as alkyl lithium (when R representa is alkyl), to provide a compound of general formula

36 em que o símbolo R representa H ou alquilo e os outros substituintes têm os significados definidos antes e se desejado, a conversão dos compostos obtidos em sais de adição de ácido aceitáveis sob o ponto de vista farmacêutico.Wherein R is H or alkyl and the other substituents are as defined above and if desired, conversion of the obtained compounds into pharmaceutically acceptable acid addition salts.

Os compostos de fórmula geral I podem ser preparados de acordo com uma variante do processo alínea a) a alínea h). e com os esquemas 1 a 8 que se seguem.. 0 material inicial está disponível comercialmente ou pode ser preparado de acordo com processos conhecidos.The compounds of formula I may be prepared according to a variant of process a) to h). and the schemes 1 to 8 which follow. The starting material is commercially available or can be prepared according to known processes.

Esquema 1Scheme 1

1. acoplamento 2. eventual eliminação de Y1. coupling 2. eventual elimination of Y

ArX rf HN°i· X: halogéneo Y: H ou grupo de protecção (por exemplo, boc)ArX: halogen Y: H or protecting group (for example, boc)

Os compostos de fórmula geral I podem ser preparados fazendo reagir derivados de piperazina de fórmula geral II corri um ácido correspondente de fórmula geral III, na presença de um agente de activação' como TBTU (2-(lH-benzotriazole-l-il)-1,1,3,3-tetrametiluróniotetrafluorobo-rato). 0 ácido de fórmula geral III pode ser preparado pela 37 reacção de um ácido de fórmula geral IV, com um álcool de fórmula geral R20H·, eventualmente na presença de um sal de cobre, tal como, Cu(I)Br. Os derivados de piperazina· de fórmula geral II podem ser preparados aquecendo a piperazina correspondente com ArX ou fazendo reagir uma piperazina protegida em N com ArX, na presença de um catalisador de paládio, seguido da clivagem de um grupo de protecção. 0 grupo de protecção é normalmente terc-butoxicarbonilo (Boc).The compounds of formula I can be prepared by reacting piperazine derivatives of Formula II with a corresponding acid of Formula III in the presence of an activating agent such as TBTU (2- (1H-benzotriazole-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate). The acid of formula III may be prepared by reacting an acid of formula IV with an alcohol of general formula R20 H, optionally in the presence of a copper salt such as Cu (I) Br. The piperazine derivatives of general formula II may be prepared by heating the corresponding piperazine with ArX or by reacting an N-protected piperazine with ArX in the presence of a palladium catalyst followed by cleavage of a protecting group. The protecting group is usually tert-butoxycarbonyl (Boc).

Esquema 2 f^NH R n X: halogéneoX is halogen

Alternativamente, os compostos· de fórmula geral I podem ser preparados por reacção de uma acilpiperazina de fórmula geral V e um álcool de fórmula geral R2OH, eventualmente, na presença de um sal de cobre, tal como, Cu(1)1. Os derivados de' acilpiperazina de fórmula geral V podem ser preparados por reacção de um ácido de fórmula geral IV com derivados de piperazina de fórmula geral II, na presença de um agente de activação, tal como, TBTU (2-(lH-benzotriazole-l-il)-1,1,3,3-tetrametiluróniotetrafluo-roborato). 38Alternatively, the compounds of formula I may be prepared by reacting an acylpiperazine of formula V and an alcohol of formula R 2 OH, optionally in the presence of a copper salt, such as Cu (1) 1. The acylpiperazine derivatives of formula V can be prepared by reacting an acid of general formula IV with piperazine derivatives of general formula II in the presence of an activating agent such as TBTU (2- (1H-benzotriazole- yl) -1,1,3,3-tetramethyluronium tetrafluoro roborate). 38

Esquema 3Scheme 3

Os compostos de fórmula geral I podem ser preparados fazendo reagir um composto de fórmula geral VI com um electrófilo de fórmula R2X, na presença de uma base, tal. como, carbonato de potássio e, eventualmente, na presença de micro-ondas, em que o símbolo X representa halogéneo, mesilato ou triflato.The compounds of formula I may be prepared by reacting a compound of formula VI with an electrophile of the formula R2X in the presence of a base, such as. such as potassium carbonate and optionally in the presence of microwaves, where X is halogen, mesylate or triflate.

Esquema 4 ii^l V O CT Αγ"ΝΊ^ R‘- R1 yVr3 1 T X D* 2 “ 1 (R :benzílo) h2 O o'H v o o-H R1 Υ'η' r5 V. rV - "TBTU r2oh CS1 R.AjAR. Mitsunobu R II Rs VIIScheme 4, wherein R 1 is hydrogen, R 2 is hydrogen, R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, .AAR. Mitsunobu R II Rs VII

3939

Os compostos de fórmula geral 1 podem ser preparados por reacção de um fenol de fórmula geral VI com um álcool, de fórmula geral R2OH, nas condições de Mitsunobu, na presença de uma fosfina, tal como, trifenilfosfina ou difenil-2-piridilfosfína e um dialquilazadicarboxilato, tal como, dietilazadicarboxilato ou di-terc-butilazodicarboxi-lato. 0 composto de fórmula geral VI pode ser preparado por desprotecção (por exemplo, utilizando hidrogénio) de um fenol protegido, tal como, um éter de benzilo (I· com R2: benzilo). Alternativamente, pode preparar-se um composto de fórmula geral VI fazendo reagir derivados de piperazina de fórmula geral· II com um ácido de fórmula geral VII, na presença- de um agentede activação, tal como, TBTU (2-(lH-benzotriazole-l-il)-1,1,3,3-tetrametiluróniotetrafluorobo-rato).Compounds of formula 1 may be prepared by reacting a phenol of formula VI with an alcohol of the formula R2 OH under Mitsunobu conditions in the presence of a phosphine such as triphenylphosphine or diphenyl-2-pyridylphosphine and a dialkylazadicarboxylate, such as diethylazadicarboxylate or di-tert-butylazodicarboxylate. The compound of formula VI may be prepared by deprotection (for example, using hydrogen) of a protected phenol, such as a benzyl ether (I, with R2: benzyl). Alternatively, a compound of formula VI may be prepared by reacting piperazine derivatives of general formula II with an acid of formula VII in the presence of an activating agent such as TBTU (2- (1H-benzotriazole- yl) -1,1,3,3-tetramethyluronium tetrafluoroborate).

ArAir

ATHE

Esquema 5Scheme 5

Os compostos de fórmula geral I podem ser preparados por fazendo reagir uma piperazina de fórmula geral VIII com ArX. 'The compounds of formula I may be prepared by reacting a piperazine of formula VIII with ArX. '

Esquema 6Scheme 6

em que o símbolo R9 representa alcoxi-(Ci-C6) ou NR7R8. 40 ίwherein R9 is (C1 -C6) -alkoxy or NR7 R8. 40 æ

Os compostos de fórmula, geral Ib em que o símbolo R9 tem o significado, defino antes, podem ser preparados fazendo reagir um ácido de fórmula geral Ia com uma amina ou um álcool correspondente, na presença de um agente de activação, tal como, carbonildimidazole.Compounds of general formula Ib in which R9 is as defined above may be prepared by reacting an acid of formula Ia with an amine or a corresponding alcohol in the presence of an activating agent such as carbonyldiimidazole .

Esquema 7Scheme 7

(d(d

Os compostos de fórmula geral Id podem ser preparados de acordo com o esquema 7 fazendo reagir um composto de fórmula geral Ic que comporta um grupo carbonilo com um composto de fórmula geral RONH2, em que o símbolo R representa H ou alquilo e o símbolo R9 representa alquilo-(Ci-Cs) , cicloalquilo-(C3-C6) , alcoxi-(Ci-C6) ou NR7Ra.Compounds of formula Id may be prepared according to scheme 7 by reacting a compound of formula Ic which bears a carbonyl group with a compound of the formula RONH2 wherein R is H or alkyl and R9 is (C 1 -C 6) -alkyl, (C 3 -C 6) -cycloalkyl, (C 1 -C 6) -alkoxy or NR 7 R a.

II

Esquema 8Scheme 8

Os compostos de fórmula geral Ie em que o símbolo R representa H ou alquilo e o símbolo R9 representa alquilo-(Ci-C5) ou cicloalquilo-(C3-Cg) podem ser preparados fazendo reagir um composto de fórmula geral Ic que comporta um grupo carbonilo, com um agente de redução, tal como, boro-hidreto de sódio (quando símbolo R representa H) ou um agente dè alquilação, tal como, alquil-lítio (quando o símbolo R representa alquilo}. 41The compounds of formula Ie wherein R is H or alkyl and R9 is (C1 -C5) -alkyl or (C3-C6) -cycloalkyl may be prepared by reacting a compound of formula Ic which comprises a carbonyl, with a reducing agent, such as sodium borohydride (when R is H), or an alkylating agent such as alkyl lithium (when R is alkyl).

As misturas racémiças dos compostos quirálicos de fórmula geral I podem ser separados utilizando CLER (cromatografia liquida de elevada resolução) quirálica.Racemic mixtures of the chiral compounds of general formula I can be separated using chiral HPLC (high performance liquid chromatography).

Os sais de adição de ácidos dos compostos básicos de' fórmula geral I podem ser convertidos nas bases livres correspondentes por tratamento com, pelo menos, um equivalente estequiométrico de uma base apropriada, tal como, hidróxido de sódio ou de potássio, carbonato de potássio bicarbonato de sódio, amónia e similares.The acid addition salts of the basic compounds of general formula I may be converted into the corresponding free bases by treatment with at least one stoichiometric equivalent of an appropriate base such as sodium or potassium hydroxide, potassium carbonate bicarbonate sodium, ammonia, and the like.

Os 660 exemplos que se seguem ilustram a presente invenção sem a limitarem. Todas as temperaturas são dadas em graus Célsius.The following 660 examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

As abreviaturas que se seguem foram utilizadas nos exemplos: TA: temperatura ambiente; n-Boc-piperazina: 1-piperazinoearboxilato de terc-bu-tilo 1; oxone®:. (peroximono-sulfato de potássio) . 2 KH S05 · KH S 0 4 *K2 S 04;The following abbreviations were used in the examples: RT: room temperature; n-Boc-piperazine: tert-butyl 1-piperazino-carboxylate 1; oxone®: (potassium peroxymonosulphate). 2 KH S05 · KH S 0 4 * K 2 S 04;

EtOAc: acetato de etilo; THF; tetra-hidrofurano; TBTU: 2- (lH-benzotriazole-1-il)-1,1,3,3-tetrametil- uróniotetrafluoroborato..; DIPEA: di-isopropiletilamina; DMF: N,N-dimetilformamida.EtOAc: ethyl acetate; THF; tetrahydrofuran; TBTU: 2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate. DIPEA: diisopropylethylamine; DMF: N, N-dimethylformamide.

Exemplo 1.1Example 1.1

Preparação de 1-(2-fluoro-4-trifluorometil-fenil)-pipera-zina 42 (a) Éster terc-butílico do ácido 4-(2-fluoro-4-trifluoro- metil-fenil)-piperazino-1-carboxllicoPreparation of 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (a) 4- (2-Fluoro-4-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid tert-

Aqueceu-se durante .16 horas, a 80 °C, uma mistura de 20 mmole de l-bromo-2-fluoro-4-trifluorometil-benzeno, 24,7 mmole de n-Boc-piperazina, 0,1 mmole de um complexo de tris(dibenzilidenoacetona)dipaládio e clorofórmio, 28,8 mmole de t-butóxido de sódio e 0,4 mmole de 2-(diciclo-hexilfosfino)bifenilo, no seio de 50 mL de tolueno. Depois de se arrefecer para a TA, tratou-se a mistura com 15 g de um soluto de HM-N e eliminaram-se todos os voláteis em vácuo. Purificou-se o resíduo em silica eluindo-se com um gradiente de heptano/EtOAc, para se obter, após evaporação, o composto do título. (b) ' 1- (2-Fluoro-4-trifluorometil-fenil) -piperazinaA mixture of 20 mmol of 1-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7 mmol of n-Boc-piperazine, 0.1 mmol of complex of tris (dibenzylideneacetone) dipalladium and chloroform, 28.8 mmol of sodium t-butoxide and 0.4 mmol of 2- (dicyclohexylphosphino) biphenyl in 50 mL of toluene. After cooling to RT, the mixture was treated with 15 g of a HM-N solution and all volatiles were removed in vacuo. The residue was purified on silica eluting with a gradient of heptane / EtOAc to give, after evaporation, the title compound. (b) 1- (2-Fluoro-4-trifluoromethyl-phenyl) -piperazine

Tratou-se uma mistura de 9 mmole do éster terc-butílico do ácido 4-(2-fluoro-4-trifluorometil-fenil)-pipe-razino-l-carboxílico, no seio de 20 mL de dioxano, com 8,93 mL de HC1 4 N, no seio de dioxano, durante 2 horas, a 8 0 0C. Concentrou-se a mistura e tratou-se com 20 mL de água, 20 mL de Na2C03 2 M e extraiu-se com 50 mL de EtOAc. Lavou-se a fase orgânica com 30 mL de NaCl saturado. Combinaram-se todas as fases orgânicas e extraíram-se com 50 mL de EtOAc. Secaram-se as fases orgânicas combinadas com MgS04 e evaporou-se, para se obter o composto do título 1.1. RMN do ^ (300 MHz, CDCl3)-5= 7,50 (d, J = 13,3 Hz, 1H, H-3), 7,45 (d, J = 8,8 Hz, 1H, H-5) , 7,16 (dd, Ji = 8,8 Hz, J2 = 8,8 Hz, 1H, H-6), 3,5-3,2 (s largo, 1H, NH), 3, 04 (m, 4H, piperazina), 2,87 (m, 4H, piperazina). EM (m/e) : 249,2 (MH+, 100 %) . 43A mixture of 9 mmol of 4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester in 20 mL of dioxane was treated with 8.93 mL of 4N HCl in dioxane for 2 hours at 80 ° C. The mixture was concentrated and treated with 20 mL of water, 20 mL of 2M Na2 CO3 and extracted with EtOAc (50 mL). The organic phase was washed with saturated NaCl (30 mL). All organic phases were combined and extracted with 50 mL of EtOAc. The combined organic phases were dried over MgSO4 and evaporated to give the title compound 1.1. NMR (300 MHz, CDCl 3) δ = 7.50 (d, J = 13.3 Hz, 1H, H-3), 7.45 (d, J = 8.8 Hz, 1H, H-5 ), 7.16 (dd, J 1 = 8.8 Hz, J 2 = 8.8 Hz, 1H, H-6), 3.5-3.2 (broad s, 1H, NH), 3.04 , 4H, piperazine), 2.87 (m, 4H, piperazine). MS (m / e): 249.2 (MH +, 100%). 43

Exemplo 1.2Example 1.2

Preparação do ácido 2-isopropoxi-5-metan.o-s-ulfonil-benzóico (a) Ácido 2-cloro-5-metano-sulfonil-benzóico A 99 mmole de ácido 2-cloro-5-(metiltio)benzóico, no seio de 400 mL de metanol, .a 0 °C, adicionou-se 296 mmole de' oxone® e deixou-se a mistura em agitação à TA, durante 3,5 horas. Filtrou-se. . o' precipitado e concentrou-se o filtrado.a pressão reduzida. Extraiu-se o resíduo 3 x com 400 mL de acetato de etilo e lavaram-se as fases orgânicas combinadas 2 x com 300 mL de HC1 1 N e com 300 mL de uma solução aquosa, saturada, de NaCl e secou-se comMgSGí. A evaporação a pressão, reduzida originou o composto do título. (b) Ácido 2-isopropoxi-5-metano-sulfonil-benzóicoPreparation of 2-isopropoxy-5-methanesulphonyl-benzoic acid (a) 2-Chloro-5-methanesulphonyl-benzoic acid To 99 mmol of 2-chloro-5- (methylthio) benzoic acid in 400 mL of methanol at 0 ° C was added 296 mmol of oxone® and the mixture was allowed to stir at RT for 3.5 hours. She filtered. . the precipitate was added and the filtrate was concentrated under reduced pressure. The 3X residue was extracted with 400 mL of ethyl acetate and the combined organic phases were washed 2X with 300 mL of 1 N HCl and with 300 mL of a saturated aqueous NaCl solution and dried with MgSO 4. Evaporation under reduced pressure gave the title compound. (b) 2-Isopropoxy-5-methanesulfonyl-benzoic acid

Aqueceu-se a 120· °C, durante 16 horas, num tubo selado, uma mistura de 2, 13 .mmole do ácido 2-cloro-5- metano-sulfonil-benzóico, 0> 64 mmole Cu(I)Br, no seio de 5 mL . de NEt3 e 25 mL de isopropanol. Eliminaram-se os voláteis em vácuo e recolheu-se o resíduo em 70 mL de HC1 1 N. A extracção com acetato de etilo, a secagem das fracções orgânicas combinadas e a evaporação, originaram um resíduo, que se purificou por CLER preparativa de fase inversa, eluindo-se com um gradiente de acetonitrilo/água. A evaporação das fracções do produto originaram o composto do título 1.2. EM (m/e.) : 257,0 (MH-, 100 %).A mixture of 2.13 g of 2-chloro-5-methanesulfonyl-benzoic acid was heated at 120 ° C for 16 hours in a sealed tube. 64 mmol Cu (I) Br in 5 mL. of NEt 3 and 25 mL of isopropanol. The volatiles were removed in vacuo and the residue collected in 70 mL of 1N HCl. Extraction with ethyl acetate, drying of the combined organic fractions and evaporation gave a residue, which was purified by preparative HPLC inverse, eluting with an acetonitrile / water gradient. Evaporation of the product fractions gave the title compound 1.2. MS (m / e): 257.0 (MH +, 100%).

Em analogia.com o exemplo 1.2 alínea (b), prepararam-se os compostos 1.3 a 1.7 do quadro que se ' segue a partir do ácido 2-cloro-5-metano-sulfonil-benzóico e o álcool apropriado: 44In analogy to Example 1.2 (b), compounds 1.3 to 1.7 of the table below were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:

Nome do composto Álcool EM (m/e) 1.3 Ácido 2-isobutoxi-5-metano-sulfonil-benzóico isobutanol 271,1 (MH", 100 %) 1.4 Ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico ciclopropil- metanol 269,1 (MH", 100 %) 1.5 Ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico 2,2,2-trifluoro-etanol 297,0 (MH", 100 %) 1.6 Ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóieo ciclopentanol 282,9 (MH“, 100 %) 1.7 Ácido 2-(4-fluoro-fenoxi)-5-metano-sulfonil-benzóico 4-fluoro-fenol (no seio de THF) 309,1 (MH", 100 %)Compound Name Alcohol EM (m / e) 1.3 2-Isobutoxy-5-methanesulfonyl-benzoic acid isobutanol 271.1 (MH ", 100%) 1.4 2-Cyclopropylmethoxy-5-methanesulfonylbenzoic acid cyclopropylmethanol 269.1 (MH ", 100%) 1.5 5-Methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid 2,2,2-trifluoroethanol 297.0 (MH ", 100 %) 1.6 2-Cyclopentyloxy-5-methanesulfonyl-benzoic acid cyclopentanol 282.9 (MH +, 100%) 1.7 2- (4-Fluoro-phenoxy) -5-methanesulfonyl-benzoic acid 4-fluoro-phenol acid (in THF) 309.1 (MH ", 100%)

Exemplo 1.8Example 1.8

Preparação de l-{3-fl:uoro-4-[4-(2-£luoro-5-nitro-benzoil)-piperazin-l-il]-fenil}-etanonaPreparation of 1- {3-fluoro-4- [4- (2-fluoro-5-nitro-benzoyl) -piperazin-1-yl] -phenyl} -ethanone

Tratou-se uma solução de 0,261 mmole de cloreto de 2-fluoro-5-nitro-benzoílo [CAS: 7304-32-7; Feng e Burgess, Chem. Europ. J. ΈΝ, 5:3261-3272 (1999)], no seio de l.ml de dioxano, com 0,522' mmole de trietilamina e depois com uma solução de 0,261 mmole de 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona (CAS: 189763-57-3; patente de invenção WO 97/14.690), no seio de 1 iriL de dioxano. Agitou-se a mistura à TA, durante 30 minutos. Eliminou-se o dissolvente in vacuo. Recolheu-se o óleo impuro em água. Extraiu-se a fase aquosa 3 vezes com CH2Cl2· Secaram-se os extractos orgânicos combinados sobre Na2S04, filtrou-se e eliminou-se o dissolvente in vacuo. Purificou-se a goma impura em gel de. sílica (eluente: heptano/acetato de etilo a 0 %-20. % (10 minutos)), para se obter o composto do título 1.8. EM (m/e): 390,2 (MH+, 100 %).A solution of 0.261 mmol of 2-fluoro-5-nitro-benzoyl chloride [CAS: 7304-32-7; Feng and Burgess, Chem. Europ. J. 5, 3261-3272 (1999)] was dissolved in 1 ml of dioxane with 0.522 mol of triethylamine and then with a solution of 0.261 mmol of 1- (3-fluoro-4-piperazin-1 -phenyl) -ethanone (CAS: 189763-57-3; WO 97/14690) was dissolved in 1 ml of dioxane. The mixture was stirred at RT for 30 minutes. The solvent was removed in vacuo. The crude oil was collected in water. The aqueous phase was extracted 3 times with CH 2 Cl 2. The combined organic extracts were dried over Na 2 SO 4, filtered and the solvent removed in vacuo. The crude gum was purified on silica gel. silica (eluent: 0-20% heptane / ethyl acetate (10 minutes)) to give the title compound 1.8. MS (m / e): 390.2 (MH +, 100%).

Exemplo 1.9Example 1.9

Preparação de (2-iodo-5-metano-sulfonil-fenil)-[4-{4-fcri-fluorometilfenil)-piperazin-l-il]-metanona 45 (a) Ácido 2-amino-5-metano-sulfonil-benzóicoPreparation of (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-fluorophenylphenyl) -piperazin-1-yl] -methanone (a) 2-Amino-5-methanesulfonyl- benzoic acid

Aqueceu-se a 125-130 °C, com agitação, durante 18 horas, uma mistura de 4,26 mmole do ácido 2-cloro-5-metano-sulfonil-benzóico, 0,39 mmole pó de cobre e 10 mL de hidróxido de amónio. Arrefeceu-se a mistura para a temperatura ambiente e filtrou-se. Lavou-se o sólido com metanol. Concentrou-se o filtrado in vácuo. Acidificou-se o resíduo com HC1 1 N até pH = 2. Lavou-se o sólido obtido com água e secou-se (HV, 50 °C, 1. hora), para se obter o composto do titulo. EM (m/e) : 214,1 (M-H, 100 %).. (b) Ácido. 2-iodo-5-metano-sulfonil-benzóico A uma suspensão de 3,0 mmole do ácido 2-amino-5-metano-sulfonil-benzóico, numa mistura de 1,7 mL de ácido' sulfúrico e 1,7 mL de água, adicionou-se, gota a gota, uma solução de 3,92 mmole de nitreto de sódio., no seio de 1,7 mL de água, numa taxa tal, que a temperatura .não excedesse 3 °C. Agitou-se a mistura a 0 °C, durante 1 hora. Adicionou-se, gota a gota, a 0 °C, uma solução de 3,0 mmole de Kl, no seio de 1,7 mL de água. Deixou-se a suspensão castanha aquecer até à TA e agitou-se durante 30 minutos. 0 excesso de iodo foi destruído pela adição de algumas gotas de uma solução de hidrogeno-sulfureto de sódio. Filtrou-se o sólido, lavou-se com água e secou-se (NV, 50 °C, 1 hora), para se obter o composto do título. EM (m/e): 325,0 (M-H, 100 %) . (c) (2-iodo-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]metanona A uma solução de 9,2 mmole do ácido 2-iodo-5-metano-sulfonil-benzóico, no seio de 20 mL de dimetilformamida, 46 adicionou-se, sucessivamente, 11,5 mmole de TBTU, 46,0 mmole de N-etildi-isopropilamina e 11,0 mmole de l-{4-trifluo-rometilfenil)piperazina (ABCR F07741NB, [30459-17- 7]). Agitou-se então a mistura reaccional à TA, durante 4 horas, concentrou-se in vacuo e purificou-se por cromatograf ia em coluna (SÍO2, 50 g, CH2Cl2/MeOH/NH3 = 100/0/0 a 95/4,5/0,5),· para se obter o composto do titulo 1.9. EM (m/e) : 539,1 (M+H+) .A mixture of 2.26 mmol of 2-chloro-5-methanesulfonyl-benzoic acid, 0.39 mmol copper powder and 10 mL of hydroxide was heated at 125-130 ° C with stirring for 18 hours. of ammonium. The mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with 1N HCl to pH = 2. The obtained solid was washed with water and dried (Hâ,,O, 50øC, 1 hour) to give the title compound. MS (m / e): 214.1 (M-H, 100%). (B) Acid. 2-iodo-5-methanesulfonyl-benzoic acid To a suspension of 3.0 mmol of 2-amino-5-methanesulfonylbenzoic acid in a mixture of 1.7 mL of sulfuric acid and 1.7 mL of water, a solution of 3.92 mmol of sodium nitride in 1.7 mL of water was added dropwise at such a rate that the temperature did not exceed 3 ° C. The mixture was stirred at 0 ° C for 1 hour. A solution of 3.0 mmol of KI in 1.7 mL of water was added dropwise at 0 ° C. The brown suspension was allowed to warm to RT and stirred for 30 minutes. The excess iodine was destroyed by the addition of a few drops of a sodium hydrogen sulfide solution. The solid was filtered, washed with water and dried (N, 50 ° C, 1 hour) to give the title compound. MS (m / e): 325.0 (M-H, 100%). (c) (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone To a solution of 9.2 mmol of 2-iodo-5 in dimethylformamide (20 mL) was added successively 11.5 mmol of TBTU, 46.0 mmol of N-ethyldiisopropylamine and 11.0 mmol of 1- (4-methylsulfonyl) trifluoromethylphenyl) piperazine (ABCR F07741NB, [30459-17-7]). The reaction mixture was then stirred at RT for 4 hours, concentrated in vacuo and purified by column chromatography (SiO 2, 50 g, CH 2 Cl 2 / MeOH / NH 3 = 100/0/0 to 95/4, 5 / 0.5) to give the title compound 1.9. MS (m / e): 539.1 (M + H +).

Exemplo 5Example 5

Preparação de [4-(2-fluoro-4-trifluorometil-fenil)-pipera-zin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanonaPreparation of [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone

Agitou-se à TA, durante 16 horas, uma mistura de 0,05 irmole 'do ácido 2-isopropoxi-5—metano-sulfonil-benzóico (composto 1.2), 0,06 mmole de 1-(2-fluoro-4-trifluorometil-fenil)-piperazina, 0,055 mmole de TBTU e 0,25 mmole de DIPEA, no seio de 1· mL de DMF. Adicionou-se 0,5 mL de MeOH/HCOOH a 1/1 e submeteu-se a mistura a uma separação por CLER preparativa de fase inversa eluindo-se com um gradiente de acetonitrilo/água, obtendo-se o composto do titulo. EM (m/e): 489,2 (MH+, 100 %).·'A mixture of 0.05 mole of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2), 0.06 mmol of 1- (2-fluoro-4- trifluoromethyl-phenyl) -piperazine, 0.055 mmol TBTU and 0.25 mmol DIPEA in 1 ml DMF. 0.5 mL of 1/1 MeOH / HCOOH was added and the mixture was subjected to reverse phase preparative HPLC separation eluting with an acetonitrile / water gradient to give the title compound. MS (m / e): 489.2 (MH +, 100%).

Em analogia com o exemplo 5, prepararam-se os compostos 1 a 4, 6 a 46 e 52 a 54 a partir dos derivados.de ácido e derivados de piperazina:In analogy to example 5, compounds 1 to 4, 6 to 46 and 52 to 54 were prepared from acid derivatives and piperazine derivatives:

Exemp. N°. Nome Sistemático Materiais Iniciais PM encont. &lt;MH+) 1 l-{3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-fenil}-etanona 1- (3-fluoro-4-piperazin--l--il“ fenil)-etanona e composto 1.2' 463,2 47 2 4- [4-(2-isopropoxi-5-meta-no-sulfonil-benzoil)-piperazin-l-il] -benzonitrilo 4-piperazin-l-il-benzonitrilo e composto 1.2 428,2 '3 3-fluoro-4-[4-(2-isopro-poxi-5-metano-sulfonil-benzoíl)-piperazin-l-il]-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.2 446,2 4 . 2-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.2 446,2 5.. [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona . 1-(2-fluoro-4-trifluorometil-fenil)-piperazina e composto 1.2 489,2 6 [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(3-fluoro-4-trifluorometil-fenil) -piperazina e composto 1.2 489,2 7 l-{3-fluoro-4-[4-(2- isobutoxi-5-metano-sulfónil-benzoil)-piperazin-l-ilj.-fenil} -etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona e composto 1.3 477,2 8 4—[4—(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo e composto 1.3 442,2 9 3-fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.3 460,3 10. 2-fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.3 460,3 11 (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina e composto 1.3 485,3 12 [4-(2-fluoro-4-trifluorometil-fenil)- 1-(2-fluoro-4-trifluorometil-fenil) -piperazina e composto 1.3 503,2 48 piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona 13 [4-(3-fluoro-4-trifluorometil- fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil) -metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina e composto 1.3 503,1 14 [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -(2-isobutoxi-5~ metano-sulfonil-fenil)-metanona 1-(2-fluoro-4-metano-sulfonil-fenil) -piperazina e composto 1.3 513,3 15 l-{4-[4-(2-ciçlopropil-metoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-fenil}-etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-ètanona'e composto 1.4 475,2 16 4- [4-(2-ciclopropilmetoxi- 5- metano-sulfonil-ben-zoil)-piperazin-l-il]-ben-zonitrilo 4-piperazin-l-il-benzonitrilo e composto 1.4 440,3 17 4- [4-(2-ciclopropilmetoxi- 5- metano-sulfonil-ben-zoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-flúoro-4-piperazin-l-il-benzonitrilo e composto 1.4 ' 458,3 IS 4- [4-^-ciclopropilmetoxi- 5- metano-Sulfonil-ben- zoil ) -piperazin-l-il]-2— fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.4 458,3 - 19 (2-ciclopropilmetoxi~5-me-tano-sulfonil-fenil) — [4—(4 — trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina e composto 1.4 483,2 20 (2-ciclopropilmetoxi-5-me-tano-sulfonil-fenil)-[4-(2-fluoro-4-trifluoro-me-tilfenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina e composto 1.4 501,2 21 (2-ciclopropilmetoxi-5-me-tano-sulfonil-fenil)-[4-(3-fluoro-4-trifluoroetil-fenil)-piperazin-l-il]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina e composto 1.4 501,2 22 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4- 1-(2-fluoro-4-metano-sulfonil-fenil) -piperazina e composto 1.4 511,3 49 (2-fluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-metanona 23 1-(3-fluoro-4-{4-[5-metane-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-íl}-fenil)-etanona l-(3-fluoro-4-piperazin-l-il-fenil)-etanona e composto 1.5 503,1 24 4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo 4-piperazin-l-il-benzoni'trilo e composto 1.5 , 468,1 25' . 3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.5 468,2 26 2-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}- benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.5 486,2 27 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil] — [4 — (4 — trifluorometil-fenil)-piperazin-l-il]-metanona 1-(.4-trifluorometil-fenil) -piperazina e composto 1.5. 511,2 28 [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1-(2-fluoro-4^trifluorometil-fenil)-piperazina e composto 1.5 529,2 . 29 [4-(3-fluoro-4-trifluoro-metil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoroetoxi)-fenil]-metanona 1- (3-fluoro-4-trifluorometil-fenil)-piperazina e composto 1.5 529,2 30 [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoroetoxi)-fenil]-metanona 1-(2-fluoro-4-metano-sulfonil- fenil)-piperazina e composto 1.5 539,2 31 l-{4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)- 1-&lt;3-fluoro-4-piperazin-l-il-fenil)-etanona e composto 1.6 489,2 50 piperazin-l-il]-3-fluoro-fenil}-etanona . 32 4 -[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-i-il]-benzonitrilo. 4-piperazin-l-il-benzonitrílo e composto 1.6 454,2 33 4-[4-(2-clclopentíloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-ll-benzonitrilo e composto 1.6 472,2 34 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin~l-il-benzonitrilo e composto 1.6 472,2 '35 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil) -piperazin-l-il] -metanona 1-(2-fluoro-4-trifluorometil-fenil )-piperazina e composto 1:6 515,2 36- (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-{3-flnoro-4^trifluorometil-fenil )-piperazin-l-il]- metanona 1-(3-flu.oro-4-trifliiorometil-fenil)-piperazina e composto 1.6 515,2 37 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil}-piperazin-l-il]-. metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina e composto 1.6 525,3 38 1-(3—fluoro-4-{4—[2—(4— fluorofenoxi) -5,-metano-sulfonil-benzoil]-piperazin-l-il}-fenil)-etanona 1-(3-fluoro-4-piperazin-l-il-ienil)-etanona e composto 1.7 515,2 '39 4- {4- [2- (4—fluoro-fenoxi)- 5- metano-sulfonil-benzoil]-piperazin-l-il}-benzonitrilo 4-piperazin-l-il-benzonitrilo e composto 1.7 480,2 40 3-fluoro-4-{4-[2-(4-fluoro-fenoxi)-5-metano-sulfonil-' benzoil]-piperazin-l-il}-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.7 498,2 41 2-fluoro-4-{4-[2-(4-fluoro-fenoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}- 2-fluoro-4-piperazin-l-il-benzonitrilo e composto 1.7 498,2 51 benzonitrilo 42 [2-(4-fluoro-fenoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluorometil-fenil) -piperazin-l-il] -metanona 1-(4-trifluorometilfenil)-piperazina e composto 1.7 523,3 43 [2-(4-fluoro-fenoxi)-5-metano-sulfonil-fenil]-[4-(2-fluoró-4-trifluorometil1-fenil)-piperazin-l-il],-metanona 1-(2-fluoro-4-trifluorometil-feníl)-piperazina e composto 1.7 541,2 44 [2-(4-fluoro-fenoxi)-5-metano-sulfonil-fenil]-[4-(3-fluoro-4-trif2uo.rometil-fenil)-piperazin-l-il]- metanona 1-(3-fluoro-4-t rifluorometil-fenil)-piperazina e composto 1.7 541,2 45 [4-(2-fluoro-4-metano-' sulfonil-fenil)-piperazin-l-il] -[2- (4-fluoro-fenoxi) -5-metano-sulfonil-fénil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil) -piperazina e composto 1.7 551,3 46 14-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il ]-( 2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(2-fluoro-4-metano-sulfonil- fenil)-piperazina e composto 1.2 499,2 52 .. 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-1-carbonil]-4-metoxi-benzeno-sulfonamicia 1-&lt;3-fluoro-4-piperazin-l-il-fenil)-etanona e ácido 2-metoxi-5-sulf amoil-benzóico 434,2 53 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-1-carbonil]-4-etoxi-benzeno-sulfonamida 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona e ácido 2-etoxi-5-sul f amoil-benz ó i co 448,2 54 1-(3-fluoro-4-14-[2-(2-metoxi-etoxi)-5-nitro-benzoil]-piperazin-l-il}-fenil)-etanona 1-(3-fluoro-4-piperazin-l-il- fenil)-etanona e ácido 2-(2-metoxietoxi)-5-nitròbenzóico 446,1Exemp. No. Systematic Name Initial Materials PM found. 1-yl) -phenyl} -ethanone 1- (3-fluoro-4-methoxyphenyl) -piperazin- piperazin-1-yl) phenyl) -ethanone and compound 1.2 '463.2472 4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] - benzonitrile 4-piperazin-1-yl-benzonitrile and compound 1.2 428.23 3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] - benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.244.6.24. 2-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.2446.2 5 - [[4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone. 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.2489.26 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5- 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.2 489.217 1 - {3-fluoro-4- [4- (2-isobutoxy-5- methanesulfonyl-benzoyl) -piperazin-1-yl} -phenyl} -ethanone 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone and compound 1.3477.88 4- [4- 2-isobutoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile and compound 1.3 442.2 9 3-fluoro-4- [4- (2-isobutoxy -5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.3 460.3 10. 2-fluoro-4- [4- (2- 1-yl] -benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile and compound 1,360,311 (2-isobutoxy-5-methanesulfonyl-benzenesulfonyl) -piperazin- (4-trifluoromethyl-phenyl) -piperazine and compound 1.3 485.3 12 [4- (2-fluoro-4 1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone hydrochloride and 1,3,5-dihydro-4-trifluoromethyl- 13 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl ) -piperazine and compound 1.3 503.1 14 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone 1 - (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and compound 1,3,53,3- {4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1 -yl] -3-fluoro-phenyl} -ethanone 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone and compound 1.4 475.2 16 4- [4- (2-cyclopropylmethoxy) -5- 1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile and compound 1.4 440.3 17 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl- sulfonylbenzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.4 '458.3 IS 4- [4- 1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.4 458.3-19 (2-cyclopropylmethoxy) Phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine and the compound 1.4483.220 ( 2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethylphenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl -phenyl) -piperazine and compound 1.4 501.2 21 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoroethyl-phenyl) -piperazin-1-yl] - methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.4 501.2 22 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methane (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (3-Fluoro-4- {4- [ 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -phenyl) -ethanone 1- (3-fluoro-4-piper azin-1-yl-phenyl) -ethanone and compound 1.5 503.1 4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin- yl} -benzonitrile 4-piperazin-1-yl-benzonitrile and compound 1.5, 468.125 '. 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro-4-piperazin-1 -yl-benzonitrile and compound 1.5 468.226 2-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} 2-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.5486.227 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- ( 4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine and compound 1.5. 511.2 28 [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.5 529.2. 29 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoroethoxy) -phenyl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.5 529.2 30 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl- -2- (2,2,2-trifluoroethoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and compound 1.5 539.2 31 1- {4- [4- 2-cyclopentyloxy-5-methanesulfonylbenzoyl) -1- &lt; 3-fluoro-4-piperazin-1-yl-phenyl) -ethanone and 1,6,49,250-piperazin-1-yl] -3-fluoro- -phenyl} -ethanone. 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile. 4-piperazin-1-yl-benzonitrile and compound 1.6 454.233 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro -4-piperazin-1-yl-benzonitrile and compound 1.6 472.234 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile 2- fluoro-4-piperazin-1-yl-benzonitrile and compound 1.6 472.235 (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin- 1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine and the compound 1: 61515, 36- (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- 1-yl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine and the compound 1.6 515.2 37 (2-cyclopentyloxy-5-methane 4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and compound 1.6 525.3 38 1- (3-fluoro-4- {4- [2- (4-fluorophenoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -phenyl} yl) -ethanone 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone and compound 1.7151539 4- {4- [2- (4-fluoro-phenoxy) -5-methane 4-piperazin-1-yl-benzonitrile and compound 1.7 480.240 3-fluoro-4- {4- [2- (4-fluoro-phenoxy) -piperazin-1-yl] 5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile and compound 1.7 498.2 41 2-fluoro-4- {4- [2- (4-fluoro-phenoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -2-fluoro-4-piperazin-1-yl-benzonitrile and the compound 1.7 498.2 51 benzonitrile 42 [2- 4-fluoro-phenoxy) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethylphenyl) -piperazine and compound 1.7 523.3 4- [2- (4-Fluoro-phenoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-trifluoromethyl-1-phenyl) -piperazin-1-yl] -methanone 1- (2- fluoro-4-trifluoromethyl-phenyl) -piperazine and compound 1.7 541.244 [2- (4-fluoro-phenoxy) -5-methanesulfonyl-phenyl] - [4- (3-fluoro-4-trifluoromethyl) -phenyl) -piperazin-1-yl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine and the compound 1.7 541.245 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [ 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and compound 1.7 551.3 46 14- (2-fluoro-2- (4-fluorophenyl) -4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone and 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and Compound 1.2 499.2 52 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-methoxy-benzenesulfonamide 1- <3-fluoro-4-piperazine yl) phenyl] ethanone and 2-methoxy-5-sulfamoyl-benzoic acid 434.2 53 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone and 2-ethoxy-5-sulfamoyl-benzylic acid 448.2 54 1- (3- fluoro-4-14- [2- (2-methoxy-ethoxy) -5-nitro-benzoyl] -piperazin-1-yl} -phenyl) -ethanone 1- (3-fluoro-4-piperazin- phenyl) -ethanone and 2- (2-methoxyethoxy) -5-nitrinobenzoic acid 446.1

Exemplo 47Example 47

Preparação de l-{3-fluoro-4-[4-(2-metoxi-5-nitro-benzoil)-piperazin-l-xl]-fenil}-etanona 52 A uma solução de 0,257 itimole de l-{3-fluoro-4-[4-(2-fluoro-5-nitro~benzoil)-piperazin-l-il]-fenil}-etanona .(composto 1.8), no seio de 1,5 mL de dioxano, adicionou-se, numa só porção, 102 mg de metóxido de sódio. Agitou-se a mistura a 100°C, durante 4 horas. Diluiu-se a mistura reaccional com. 10 mL de água, neutralizou-se com HC1 1 N e depois extraiu-se com acetato de etilo (3 . x 10 mL). Concentraram-se as fases orgânicas combinadas in vacuo. Fez-se a cromatografia do resíduo em gel de sílica: eluente* heptano/acetatò de etilo a 0 %-30 % (10 minutos), para se obter o composto 47. EM (m/e): 402,2 (M+H+, 100 %) .Preparation of 1- {3-fluoro-4- [4- (2-methoxy-5-nitro-benzoyl) -piperazin-1-yl] -phenyl} -ethanone To a solution of 0.257 g of 1- {3- fluoro-4- [4- (2-fluoro-5-nitro-benzoyl) -piperazin-1-yl] -phenyl} -ethanone (compound 1.8) in 1.5 mL of dioxane was added, in one portion, 102 mg of sodium methoxide. The mixture was stirred at 100 ° C for 4 hours. The reaction mixture was diluted with. 10 mL of water, neutralized with 1 N HCl and then extracted with ethyl acetate (3.times.10 mL). The combined organic phases were concentrated in vacuo. The residue was chromatographed on silica gel: eluent * heptane / ethyl acetate at 0-30% (10 minutes) to give compound 47. MS (m / e): 402.2 (M + H +, 100%).

Exemplo 48Example 48

Preparação de {2-benziloxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometilfenil)-piperazin-l-il]-metanonaPreparation of {2-benzyloxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone

Aqueceu-se a 110 °C, durante 16 horas, uma mistura de ,0,19 mmole de (2-iodo-5-metano-sulfonil-fenil)-[4-(4- trifluorometilfenil)-piperazin-l-il]-metanona . u ' (composto 1.9), 0,037 mmole de· Cul, .0,37 mmole de CS2CO3, 0, 074 mmole de . 1,10-fenantrolina ' e 0,4 mL de álcool, benzilico. Arrefeceu-se a mistura para a TA, diluiu-se com acetato ,dé etilo. e filtrou-se. Lavou-se a camada orgânica duas vezes com água, secou-se sobre Na2S04, . filtrou-se e eliminou-se o dissolvente in vacuo. Purificou-se o óleo impuro em gel de sílica, eluente: heptano/acetato de etilo a 0 %-50 %' (25 minutos), para se obter o composto 48. EM (m/e): 519,2 (M-H+, 100 %) .A mixture of 0.19 mmol (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone was heated at 110 ° C for 16 hours. -methanone. (compound 1.9), 0.037 mmol Cul, .0.37 mmol CS2 CO3, 0.074 mmol. 1,10-phenanthroline and 0.4 ml of benzyl alcohol. The mixture was cooled to RT, diluted with ethyl acetate. and filtered. The organic layer was washed twice with water, dried over Na2 SO4. filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel eluent: 0-50% heptane / ethyl acetate (25 minutes) to give compound 48. MS (m / e): 519.2 (M- H +, 100%).

Em analogia com· o exemplo. 48, prepararam-se os compostos 49 a 51 do quadro que segue a partir de (2-íodo-· 5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-pipe-razin-l-il]-metanona (composto 1.9) e álcoois: 53In analogy with the example. 48, compounds 49 to 51 of the table below were prepared from (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -methanone (compound 1.9) and alcohols: 53

Exemp. N°. Nome Sistemático Materiais Iniciais PM aacont. (MH+) 49 (2-etoxi-5~metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-1-il]-metanona composto 1.9 e etanol 457,2 50 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona composto 1.9 e álcool isopropilico 471,2 51 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-(4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona composto 1.9 e ciclo-pentanol 497,2Exemp. No. Name Systematic Initial Materials PM aacont. (MH +) 49 (2-ethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone Compound 1.9 and ethanol 457.250 (2-isopropoxy- 5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone Compound 1.9 and isopropyl alcohol 471.2 51 (2-cyclopentyloxy-5-methanesulfonyl- - (4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone Compound 1.9 and cyclopentanol 497.2

Exemplo 1.10Example 1.10

Preparação do ácido 5-metano-sulfonil-2-{2-metoxi-etoxi)-benzóico (a) Ácido 2-Ãmino-5-metano-sulfonil-benzóicoPreparation of 5-Methanesulfonyl-2- {2-methoxy-ethoxy) -benzoic acid (a) 2-Amino-5-methanesulfonyl-benzoic acid

Aqueceu~se a 125-130 °C, com agitação, durante 18 horas, uma mistura de 4,26 mmole do ácido 2-cloro-5-metano-sulfonil-benzóico (composto 1.2a), 0,39 mmole de pó de cobre e 10 mL de hidróxido de amónio a 25 %. Arrefeceu-se a mistura para a temperatura ambiente e filtrou-se. Lavou-se o sólido com metanol. Concentrou-se o filtrado in vacuo. Acidificou-se o resíduo com HC1 1 N até pH = 2. Lavou-se o sólido obtido com água'e secou-se {HV, 50 °C, 1 hora), para se obter o composto do titulo. EM (m/e): 214,1 (M-H, 100 %) · (b) Ácido 2-iodo-5-metano-sulfonil-benzóico A uma suspensão de 3,0 mmole do ácido 2-amino-5-metano-sulfonil-benzóico, no seio de uma mistura de 1,7 mL de ácido sulfúrico e 1,7 mL de água, adicionou-se, gota a gota, uma solução de 3,92 mmole de nitreto de sódio, no 54 seio de 1,7 mL de água a uma velocidade tal que a temperatura' não excedesse 3 °C. Agitou-se a mistura a 0 °C, durante 1 hora. Adicionou-se, gota a gota, uma solução de 3,0 mmole de Kl, no seio de 1,7 mL de água, a 0 °C. Deixou-se a suspensão castanha aquecer até à TA e agitou-se durante 30. minutos. Destruiu-se o excesso de iodo por adição' de algumas gotas de uma solução de hidrogeno-sulfureto de sódio. Filtrou-se o sólido, lavou-se.com água e secou-se (HV, 50 °C, 1 hora), para se obter o composto do título. EM (m/e) : 325,0 (M-H, 100 %') . (c) Ácido 5&quot;metano&quot;Sulfonil-2-(2-metoxi-etoxi)-benzóico A uma solução de 1,6 mmole do ácido 2-iodo-5-metano-sulfonil-benzóico, no seio de 30 mL de 2-metoxietanol e 6 mL de tr.ieti lamina,' adicionou-se' 79 mg de brometo de cobre, (í) e aqueceu-se a mistura reaccional a 120°C, durante 4 horas. Destilou-se' o dissolvente e dissolveu-se o resíduo no seio de 90 mL de HC1 l'N. Extraiu-se a fase aquosa duas vezes com acetato de. etilo e lavaram-se os extractos orgânicos combinados, duas vezes com água e uma vez com salmoura. Secou-se a camada orgânica com Na2S04, filtrou-se e vaporou-se, para se obter o composto do título 1.10, EM (m/e) : 273, 1..(MH”, 100 %) .A mixture of 2-chloro-5-methanesulfonyl-benzoic acid (Compound 1.2a), 0.39 mmol of potassium carbonate (Compound 1.2a) was heated at 125-130 ° C with stirring for 18 hours. copper and 10 mL of 25% ammonium hydroxide. The mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with 1 N HCl to pH = 2. The obtained solid was washed with water and dried (HV, 50øC, 1 hour) to give the title compound. (B) 2-iodo-5-methanesulfonyl-benzoic acid To a suspension of 3.0 mmol of 2-amino-5-methanesulfonyl- sulfonyl benzoic acid in a mixture of 1.7 mL of sulfuric acid and 1.7 mL of water was added dropwise a solution of 3.92 mmol of sodium nitride in 1% , 7 mL of water at such a rate that the temperature did not exceed 3 ° C. The mixture was stirred at 0 ° C for 1 hour. A solution of 3.0 mmol of KI in 1.7 mL of water was added dropwise at 0 ° C. The brown suspension was allowed to warm to RT and stirred for 30 minutes. The excess iodine was destroyed by the addition of a few drops of a sodium hydrogen sulphide solution. The solid was filtered, water washed and dried (HV, 50øC, 1 hour) to give the title compound. MS (m / e): 325.0 (M-H, 100%). To a solution of 1.6 mmol of 2-iodo-5-methanesulfonyl-benzoic acid in 30 mL of 2- (2-methoxy-ethoxy) -benzoic acid -methoxyethanol and 6 ml of triethylamine were added 79 mg of copper bromide, (i), and the reaction mixture was heated at 120 ° C for 4 hours. The solvent was distilled off and the residue dissolved in 90 mL of 1N HCl. The aqueous phase was extracted twice with ethyl acetate. ethyl acetate and the combined organic extracts were washed twice with water and once with brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound 1.10, MS (m / e): 273.1 (MH +, 100%).

Exemplo 1.11Example 1.11

Preparação do ácido 5-ciano-2~(2-metoxi-etoxi)-benzóico (a) Ácido 2-bromo-5-ciano-benzóico A uma suspensão de 7,1 mmole de brometo de cobre (II), no seio de acetonitrilo (30 mL), adicionou-se, gota a gota, 8,63 mmole de nitrito: de terc-butilo, a 0 °C, durante 2 55 minutos. Adicionou-se, numa só porção, 6,17 mmole do ácido 2-amino-5-ciano-benzóico (CAS: 99767-45-0; ' patente de invenção WO 9518097), durante 10 minutos, a 0 °C. Agitou-se a mistura a 0 °C, durante 2 horas e depois à temperatura ambiente durante a noite. Eliminou-se metade do dissolvente in vácuo. Recolheu-se o residuo em HC1 1 N (15 mL) e acetato de etilo (30 mL) . Extraiu-se a camada orgânica com NaOH 1 N (3 x 10 mL) . Acidificou-se a camada orgânica com HC1 2 N. Filtrou-se o sólido resultante, lavou-se com água e secou-se (vácuo forte, 50 °C) , para se obter o composto do titulo. EM (m/e) : 227,1 (M+H+, 100 %) . (b) Ácido 5-ciano-2-(2-metoxi-etoxi)-benzóico A uma solução de 0,16 mmole do' ácido 2-bromo-5-ciano-benzóico, no seio de 6 mL de 2-metoxieta.no 1 e 1,2 mL de trietilamina, adicionou-se 23 mg de brometo de cobre (.1) e aqueceu-se a mistura reaccional até 120 °C, durante 4 horas. Destilou-se o dissolvente dissolveu-se o resíduo no seio de 20 mL de HC1 1 N. Extraiu-se a fase aquosa duas vezes com acetato de etilo e lavaram-se os extractor orgânicos combinados duas vezes com água e uma vez com salmoura. Secou-se a camada orgânica com Na2SC&gt;4, filtrou-se e evaporòu-se, para se obter o' composto do titulo 1.11. EM (m/e) : 220,4 (MH&quot;r 100 Exemplo 1.12Preparation of 5-Cyano-2- (2-methoxy-ethoxy) -benzoic acid (a) 2-Bromo-5-cyano-benzoic acid To a suspension of 7.1 mmol copper (II) bromide in acetonitrile (30 mL), 8.63 mmol of tert-butyl nitrite was added dropwise at 0 ° C for 55 minutes. 2-Amino-5-cyano-benzoic acid (CAS: 99767-45-0; WO 9518097) was added in one portion over 10 minutes at 0 ° C. The mixture was stirred at 0 ° C for 2 hours and then at room temperature overnight. Half of the solvent was removed in vacuo. The residue was taken up in 1N HCl (15 mL) and ethyl acetate (30 mL). The organic layer was extracted with 1N NaOH (3 x 10 mL). The organic layer was acidified with 2N HCl. The resulting solid was filtered, washed with water and dried (aq. Vacuum, 50øC) to give the title compound. MS (m / e): 227.1 (M + H +, 100%). (b) 5-Cyano-2- (2-methoxy-ethoxy) -benzoic acid To a solution of 0.16 mmol of 2-bromo-5-cyano-benzoic acid in 6 mL of 2-methoxyethoxy. in 1 and 1.2 mL of triethylamine was added 23 mg of copper (.1) bromide and the reaction mixture was heated to 120 ° C for 4 hours. The solvent was distilled off and the residue was dissolved in 20 ml of 1 N HCl. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were washed twice with water and once with brine. The organic layer was dried over Na2 SO4, filtered, and evaporated to give the title compound 1.11. MS (m / e): 220.4 (MH &quot; r 100 Example 1.12

Preparação do ácido 5-ciano-2-(2,2,2-trifluoro-etoxi)-benzóicoPreparation of 5-Cyano-2- (2,2,2-trifluoro-ethoxy) -benzoic acid

Aqueceu-se a. 100 : °C uma mistura de 11,3 mmole de sódio, no seio de 66 mmole de 2,2,2-trifluoroetanol até o sódio -ter sido dissolvido (20 minutos). Depois, adicionou-se uma solução de 5,5 mmole de ácido 5-ciano-2-iodo- 56 benzóico [CAS: 219841-92-6; WO 9901455], no seio de 2 mL de N-metil-2-pirrolidona e 0,5 mmole de brometo de cobre (I) e aqueceu-se a mistura reaccional até 120° C, durante 2 horas. Verteu-se a mistura reaccional em água, acidificou-se até pH 2 com HC1 concentrado e extraiu-se 3x com acetato de etilo. Lavaram-se os extractos orgânicos combinados com salmoura, secaram-se sobre Na2S04 e evaporaram-se. A cromatograf ia à pressão em gel de sílica com heptano/acetato de etilo, originou o composto do titulo 1.12. EM (EI) (m/e) : 245, 1 (Μ*, 94 %) , 14.6,0 ( [M-CF3CH20]+, 100 %) . ; Em analogia com o exemplo 1.12, prepararam-se os compostos 1.13. a 1.16 do quadro que se segue a partir do ácido 5-ciano-2-íodo-benzólco e do álcool apropriado:It warmed up. 100 ° C a mixture of 11.3 mmol of sodium in 66 mmol of 2,2,2-trifluoroethanol to the sodium was dissolved (20 minutes). Then, a solution of 5.5 mmol of 5-cyano-2-iodo-benzoic acid [CAS: 219841-92-6; WO 9901455] was dissolved in 2 mL of N-methyl-2-pyrrolidone and 0.5 mmol of copper (I) bromide and the reaction mixture was heated to 120 ° C for 2 hours. The reaction mixture was poured into water, acidified to pH 2 with concentrated HCl and extracted 3x with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. Flash chromatography on silica gel with heptane / ethyl acetate afforded the title compound 1.12. MS (EI) (m / e): 245.1 (Μ *, 94%), 14.6.0 ([M-CF3 CH2 O +, 100%). ; In analogy to example 1.12, compounds 1.13 were prepared. to 1.16 of the following table from 5-cyano-2-iodo-benzoic acid and the appropriate alcohol:

Nome do composto Álcool SM (m/e) 1.13 ácido o-2-isopropoxi-benzóico isopropanol 204,1 (M-H~, 100 %) 1.14 ácido 5-ciano-2-ciclopropil-metoxi-benzóico ciclopropiΙ-metanol 216,1 (M-hV 100 %) 1.15 ácido 5-ciano-2-isobutoxi-benz.óico álcool isobutilicq 218,3 (M-H~, 100 %) 1.16 ácido 5-ciano-2-ciclopentiloxi-benzdico ciclopentanol 230,1, (Μ-ΕΓ, ’l00 %)Compound Name Alcohol SM (m / e) 1.13 o-2-isopropoxy-benzoic acid isopropanol 204.1 (MH +, 100%) 1.14 5-cyano-2-cyclopropylmethoxy-benzoic acid cyclopropylmethanol 216.1 ( 5-cyano-2-isobutoxy-benz oic acid isobutyl alcohol 218.3 (MH +, 100%) 1.16 5-cyano-2-cyclopentyloxy-benzic acid cyclopentanol 230.1, ΕΓ, '100%)

Em analogia com o exemplo 5,' prepararam-se os compostos .55 a 61 do quadro que se segue a partir dos derivados de ácido e derivados de piperazina:In analogy to example 5, compounds 55 to 61 of the following table were prepared from the acid derivatives and piperazine derivatives:

Exemp. N° . Nome Sistemático Materiais Iniciais PM encont. (MH+) 55 1-(3-fluoro-4-{4-[5-metano-sulfonil-2-(2-metoxi-etoxi)-benzoil]-piperazin-l-il}-fenil)-etanona. l-(3-fluoro-4-piperazin-l-il-fenil)-etariona (WO9714690) e ácido 5-metano-sulfonil-2- (2-metoxi-etoxi)-benzóico (composto 1.10) 479,5 56 4-(2-Metoxi-etoxi)-3-[4-{4- 1-(4-trifluorometil-l-(4- 434,5 57 trifluorometil-fenil)-piperazino-l-carbonil]-benzonitrilo trifluorometil-5-fenil}-piperazina e ácido 5-ciano-2-(2-metoxi-etoxi)-benzóico (composto 1.11} 57 4-(2,2,2-Trifluorc&gt;-etoxi) -3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzonitrilo 1- (4-trlfluorQmetilfenil)-piperazina e ácido 5-ciano-2-(2/2,2-trifluoro-etoxi)-benzóico (composto 1.12) 458,4 58 4-isopropoxi-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzonitrilo 1-(4-trifluorometilfenil)-piperazina e ácido 5-ciano-2-isopropoxi-benzóico (composto 1.13) 418,3 59 4-ciclopropilmetoxi-3-[4-(4-trifluorometil-fenil·)-piperazino-l-carbonil]-benzonitrilo 1- (4-trifluorometilfenil)-piperazina e ácido 5-ciano-2-ciclopropilmetoxi-benzóico (composto.1.14) 430,6 60 4-isobutoxi-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzonitrilo 1-(4-trifluorometilfenil)-piperazina e ácido 5-ciano-2-isobutoxi-benzóico (composto 1.15) 432,5 61 ' 4-ciclopentiloxi-3- (4- (4-trifluorometil-fenil)-piperazino-l-carbonil]-benzonitrilo 1-(4-trifluorometilfenil)-piperazina e ácido 5-ciano-2-ciclopentiloxi-benzóico (composto 1.16) 444,5Exemp. No. Systematic Name Initial Materials PM found. (MH +) 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (2-methoxy-ethoxy) -benzoyl] -piperazin-1-yl} -phenyl) -ethanone. 5-methanesulfonyl-2- (2-methoxy-ethoxy) -benzoic acid (compound 1.10) 479.5 564 (4-trifluoromethyl-1- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzonitrile trifluoromethyl-5- (2-methoxy- phenyl} -piperazine and 5-cyano-2- (2-methoxy-ethoxy) -benzoic acid (compound 1.11) 4- (2,2,2-Trifluoroc-ethoxy) -3- [4- (4-trifluoromethyl phenyl) -piperazine-1-carbonyl] -benzonitrile 1- (4-trifluoromethylphenyl) piperazine and 5-cyano-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.12) 4-isopropoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzonitrile 1- (4-trifluoromethylphenyl) -piperazine and 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) , 3 59 4-cyclopropylmethoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzonitrile 1- (4-trifluoromethylphenyl) -piperazine and 5-cyano-2-cyclopropylmethoxy-benzoic acid ( compound.1.14) 430.6 60 4-Isobutoxy-3- [4- (4-trifluoromethyl-phenyl) - piperazine-1-carbonyl] -benzonitrile 1- (4-trifluoromethylphenyl) piperazine and 5-cyano-2-isobutoxybenzoic acid (compound 1.15) 432.5 61 '4-cyclopentyloxy-3- (4- (4-trifluoromethyl) -phenyl) -piperazine-1-carbonyl] -benzonitrile 1- (4-trifluoromethylphenyl) -piperazine and 5-cyano-2-cyclopentyloxy-benzoic acid (compound 1.16)

Exemplo 2.1Example 2.1

Preparação de (2-hidroxi-5-nifcro-fenil)-[4-(4 trifluorome-til-fenil)-piperazin-l-il]-metanonaPreparation of (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone

Preparou-se o composto 2.1 em analogia com o exemplo 5. utilizando o ácido 2-hidroxi-5-nitrobenzóico [96-97-9] e 1- (4-trifluorometil-fenil) -piperazina. EM (m/e) : 394,0 (M^- H, 100 %) .Compound 2.1 was prepared in analogy to example 5 using 2-hydroxy-5-nitrobenzoic acid [96-97-9] and 1- (4-trifluoromethyl-phenyl) -piperazine. MS (m / e): 394.0 (M + H, 100%).

Exemplo 2.2Example 2.2

Preparação de (2-hidroxi-5-metano-sulfonil-fen.il) - [4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 58 . Preparou-se o composto 2.2 em analogia com o exemplo .5&quot;. utilizando o ácido 2-hidroxi-5-(metilsulfonil)benzóico [68029-77-6] e 1-(4-trifluorometil-fenil)-piperazina. EM (m/e): 427,5 (M-H, 100 %).Preparation of (2-hydroxy-5-methanesulfonylphenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 58. Compound 2.2 was prepared in analogy to example 5 &quot;. using 2-hydroxy-5- (methylsulfonyl) benzoic acid [68029-77-6] and 1- (4-trifluoromethyl-phenyl) -piperazine. MS (m / e): 427.5 (M-H, 100%).

Exemplo 66Example 66

Preparação de {2-butoxi-5^n±tro-fenil)-[4-(4-trifltiorome-til-fenil)-piperazin-l-il]-metanonaPreparation of (2-butoxy-5-nitrophenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone

Aqueceu-se a 15 0 °C, durante 15 minutos, num forno de micro-ondas, uma solução de (2-hidroxi-5-nitro-fenil)-[4-(4-trif luorometil-fenil)·-piperazin-l-il ]-metanona (50 mg), carbonato de potássio (87 mg). e 1-bromobutanò (0,15 mL), no seio de dimetilacetamida (0,3 mL).A solution of (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] 1-yl] -methanone (50 mg), potassium carbonate (87 mg). and 1-bromobutane (0.15 mL) in dimethylacetamide (0.3 mL).

Concentrou-se então a mistura reaccional e purificou-se por cromatografia em coluna (Si02) , para se obter o composto do título (55 mg).The reaction mixture was then concentrated and purified by column chromatography (SiO2) to provide the title compound (55 mg).

Em analogia com o exemplo 66, prepararam-se os compostos 62 a 97 do quadro que se segue a partir de derivados de ácido e derivados de piperazina:In analogy to example 66, compounds 62 to 97 of the following table were prepared from acid derivatives and piperazine derivatives:

Exemp. r. Nome Sistemático Materiais Iniciais PM encont. (MH+) 62 (2-isopropoxi-5-nitro-fe-nil)-[4-(4-trifluorometil-fenil) -piperazin-l-il]-metanona e piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)—[4—( t rif luorometil-feiiil) -piperazin- 1- il]-metanona (composto 2.1) e 2- bromopropano 438,4 63 (2-ciclopropilmetoxi-5-nitro-fenil)-[4-(4-tfifluorometil-fenil)-piperazin-l-il] metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona {composto 2.1) e brometo de ciclopropil-metilo 450,5 64 (2-ciclobutilnietoxi-5-nitro-fenil)-[4-(4-trifluorometil- (2-hidroxi-5-nitro-fenil)-[4-4-tri f iuorometi1-feni1)-pipera zin- 464,5 ' 59 fenil)-piperazin-l-il]-metanona 1-il)-metanona (composto 2.1) e brometo de ciclobutil-metilo 65 (2-aliloxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-metano-sulfonil-fe-nil)-[4-(4-trifluorometil-fe-nil)-piperazin-l-il] -metanona (composto 2.2) e brometo de ciclopropilo 469,5 66 &lt;2-butoxi-5-nitro-fenil)-[4-(4-trifluorometil-fe-nil)-piperazin-l-il]-meta-nona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e bromobutano 452,4. 67 rac-[2-(2-h.idro-propoxi) -5-nitro-fenil]-[4-(4-trifluo-rometil-fenil)-piperazin-l- il] -metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e rac-l-bromo-2-propanol 454,6 68 [2-(2,2-dimetil-propoxi) -5-nitro-fenil]-[4-(4-trifluo-rometil-fenil)-piperazin-l- il] -metanona (2-hidroxi-5-nitro-fenil)-[4-4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e 1-bromo-,2-dimet ilpropano 466,6 69 [2-(3-metil-butoxi)-5-ni-tro-fenil]-[4-(4-trifluoro- · metil-fenil)-piperazin-l-il] -metanona (2-hidroxi-5-nitro-fenil)-[4-4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e l-bromo-3-metilbutano 466,5 70 (2-isobutOxi-5-nitro-fe- nil)-[4-(4-trifluorometil-' fenil)-piperazin-l-il] metanona (2-h.idroxi-5-nitro-fenil) — [ 4— (4— trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e l-bromo-3-metilpropano 452,5 71 (2-ciclopentiloxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil).- [4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e brometo de ciclopentilo 464,5 72 (5-nitro-2-propoxi- triflnorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil) — [4 —{4— trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e 1-bromopropano 438,5 73 (2-ciclo-heptiloxi-5-iiitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e bromociclo-heptano 492,5 74 (2-ciclobutoxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]- (2-hidroxi-5-nitro-fenil)-[4-(4-trifluoromètil-fenil)-piperazin-l-il] -metanona (composto 2.1) e 450,4 60 metanona bromociclobutano 75 [2-(2-etoxi-etoxi)-5-nitro-fenil] - [4- (4-trifluorometil-fenil) -piperazin-l-il] -metanona {2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e éter de 2-bromoetil-etilo 468.,5 76 [2-((R)-3-hidroxi-2-metil-propoxi)-5-nitro-fenil]-[4-(4-trifluorometil-fenil).-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-fenil)[4-4-trifluorometil-fenil)-piperazin-l-il]-metanona (composto 2.1) e (R) - (-) -3-bromo-2-metil-l-propanol 468,4 77 (2-etoxi-5-nitro-fenil)—[4— (4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)—[4—(4— trifluorometil-fenil)-piperazin- 1- il] -metanona : (composto 2.1) e 2- bromo-l-etoxi-l,1,2-trifluoro-etano 424,4 78 rac-(2-sec-butoxi-5-nitro-fenil)-[4-(4-trifluorome-til-f enil ) -piperazin-l-il ] metanona rac-(2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il]-(2.1) e metanona (composto 2.1) e 2-bromobutano 452,5 79 (2-(2-hidroxi-etoxi)-5-nitro-fenil] -[4- (4-trifluoro- . metil-fenil)-piperazin-l-il] -metanona (2-hidroxi-5-nitro-fénil)-[4-(4-trifluorometil-fenil)-piperazin- 1- il] -metanona (composto 2.1) e 2- bromo-l-etanol 440,4 80 [5-Nitro-2-(2,2,3,3-tetra-fluoro-propoxi)-fenil]- [4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-£eail)-(4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e l-iodo-2,2,3,3,-tetrafluoroprop.ano 510,5 81 (5-nitro-2-(4,4,4-trifluoro-butoxi)-fenil]-[4- (4-trifluorometil-fenil)-piperazin^l-il]-metanona (2-hidroxi-5-nitro-fenil) — [ 4—4 — trifluorometil-fenil)-piperazin-1-fenil)-il]-metanona (composto 2.1) e l-bromo-4,4,4,-trifluorobutano 506,5 82 [2-(2-fluoro-etoxi)-5-nitro-fenil] -[4-(4-trifluorometil-fenil ) -piperazin-l-il ] -metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e l-bromo-2-fluoroetano 442,5 83 [2-(3-hidroxi-2,2-dimetil-propoxi)-5-nitro-fenil]-[4-. (4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trif luorometil-fenil.) -piperazin-l-il]-metanona· (composto 2.1) e 3-bromo-2,2-dimetil-2-propan-l-ol 482,6 84 [5-nitro-2-(2,2, 2-trifluoro- (2-hídroxi-5-nitro-fenil) -[4-(4- 478,3 61 etoxi)-fenil]-[4-(4-trif luoroiaetil-f enil) -piperazin-1-il]-etanona tri fluorome ti1-fenil)-pipera z in-1-il]-metanona (composto 2.1) e 1,1, l-trifluoro-2-jodo-etano 85 [2-(1-Etil-propoxi)-5-nitro-fenil]-[4-(4-trifluorometil-fenil) -piperazin-l-il] -metanona (2-hidroxi-5-nitro-fenil)—[4—(4— tri fluo rome ti1-feni1)-pipe raz in-1-il]-metanona (composto 2.1) e 3-bromo-pentano 466,5 86 [5-nitro-2-(oxetan-3-iloxi)-fenil] - [4- (4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e éster oxetan-3-ilico do ácido tolueno-4-sulfónico (CAS: 26272-83-3) 452,4 87 [2-(3-hidrCxi-propoxi)-5-nitro-fenil]-[4-(4- trifluorometil-fenil)-piperazin-l-il]-metanona (2-h.idroxi-5-nitro-fenil) — [4— (4— trifluorometil-fenil)-piperazin-l-il ] -metanona (composto 2.1) e bromopropanole . 454,6 88 . [2-(biciclo[2.2.1]hept-2-iloxi)-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e exo-2-bromonorbornano 490,5 89 [2-(2-metoxi-etoxi)-5-nitro-fenil] -.[4- (4-trifluorometil-fenil)-pipèrazin-l-il]- metanona ' (2-h.idroxi-5-nltro-fenil) - [4- (4-trifluorometil-fenil)-pipe-razin-1-il)-metanona (composto 2.1) e éster 2-bromoetilmetílico 454,5 90 . [2-(3,3-dimetil-butoxi)-5-nitr.o-fenil]-[4-(4-trif luorometil-feniD-piperazin-l-il] -metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e l-bromo-3,3-dimetilbutano 480,8 91 [2-(1-etoxi-ciclopropoxi)-5-nitro-fenil]-[4-(4-trifluorometil-fenil) -piperazin-l-il]-metanona (2-h.idroxi-5-nitro-fenil) - [4- (4-trifluorometil-fenil)-piperazin-1-il-metanona (composto 2.1) e 1-bromo-1-etoxi-ciclo-prop'ano 480,6 92 [2-(2-cloro-etoxi)-5-nitro-fenil] - [4- (4-trifluoro-metil-fenil)-piperazin-1-ilj-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin- 1- il] -metanona (composto 2.1) e 2- cloroetanol 458,4· 93 {4-nitro-2-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-fenoxi}-acetonitrilo (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e brómoacetonitrilo 435,4 94 5-nitro-2-(3,3,3-trifluoro-propoxi)-fenil]- [4- (4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)—[4—(4— trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2,1) e 1,1,1-trifluoro-l-iodopropano 492,4 62 95 [5-nitro-2-(tetra-hidro-piran-4-iloxi) -fenil] — 14— (4— trifluorometil-fenil)-piperazin-l-il]-metanona (2-h.idroxi-5-nitro-fenil) -[4~ (4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e 4-cloro-tetra-hidropirano 460,4 96 [2-(2,2-difluoro-etoxi)-5-nitro-fanil]-[4-(4-trifluorometil-fenil) -piperazin-l-il]-metanona (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin- 1-il]-metanona (composto 2.1) e l-bromo-2,2-difluoroetano 460,5 97 [2— (1,1,2,3,3,3-hexafluoro-propoxi)-5-nitro-fenil]-[4-(4-tri£luorometil-fenil)-piperazin-l-il]-metanona (2-Hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (composto 2.1) e 3-hexafluoropropano 5.46,3Exemp. r. Systematic Name Initial Materials PM found. (MH +) 62 (2-isopropoxy-5-nitrophenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone and piperazin-1-yl] -methanone (2-hydroxy -5-nitro-phenyl) - [4- (trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 2-bromopropane 438.463 (2-cyclopropylmethoxy-5- - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and cyclopropylmethyl bromide 450.5 64 (2-cyclobutylnomethoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl- (2-hydroxy-5-nitrophenyl) - [4- 1-yl] -methanone 1-yl) -methanone (compound 2.1) and cyclobutyl-methyl bromide 65 (2-allyloxy-5-methylphenyl) -piperazin- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl- yl) -piperazin-1-yl] -methanone (compound 2.2) and cyclopropyl bromide 469.566 <2-butoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) ) (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and bromobutane 452, 4. Rac rac [2- (2-hydroxy-propoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5- phenyl) -piperazin-1-yl] -methanone (compound 2.1) and rac-1-bromo-2-propanol 454.6 [2- (2,2- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- 1-yl] -methanone (compound 2.1) and 1-bromo-, 2-dimethylpropane 466.669 [2- (3-methyl-butoxy) -5-nitro-phenyl] -piperazin- ] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4-4-trifluoromethyl-phenyl) -piperazin- yl] -methanone (compound 2.1) and 1-bromo-3-methyl butane 466.5 70 (2-isobuthoxy-5-nitrophenyl) - [4- (4-trifluoromethylphenyl) piperazin- yl] methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1-bromo-3-methylpropane 452, (2-cyclopentyloxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and cyclopentyl bromide 464.5 (5-nitro-2-propoxy) (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1-bromopropane 438.5 73 (2-cycloheptyloxy-5-yl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl ) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and bromocycloheptane 492.5 74 (2-cyclobutoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) , 460 methanone bromocyclobutane 75 [2- (2-ethoxy-ethoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5- nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 2-bromoethyl-ethyl ether 468.576 [2 - ((R) -3 hydroxyl 2-methyl-propoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) [(4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and (R) - (-) - 3-bromo-2-methyl-1-propanol 468.477 (2-ethoxy -5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) - piperazin-1-yl] -methanone: (compound 2.1) and 2-bromo-1-ethoxy-1,1,2-trifluoroethane 424.48 rac- (2-sec-butoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone rac- (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1 -yl] - (2.1) and methanone (compound 2.1) and 2-bromobutane 452.579 (2- (2-hydroxyethoxy) -5-nitro-phenyl] - [4- (4-trifluoro- methyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 2- bromo-1-ethanol 440.4 80 [5-Nitro-2- (2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1 (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1-iodo-2,2-dimethyl- 3,3, -tetrafluoropropane 510.5 81 (5-nitro-2- (4,4,4-trifluoro-butoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -methanone (compound 2.1) and 1-bromo-4,4,4-trifluoromethyl-phenyl) -piperazin-1-yl) -methanone (2-fluoro-ethoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5- 4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1-bromo-2-fluoroethane 442.5 [2- (3-hydroxy-2- , 2-dimethyl-propoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) (compound 2.1) and 3-bromo-2,2-dimethyl-2-propan-1-ol 482.6 84 [5-nitro-2- (2,2,2-trifluoro- (2-hydroxy-5-nitro -phenyl) - [4- (4-naphthalen-4-yl) -phenyl] - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -ethanone trifluoromethylphenyl) -piperazine 1-yl] -methanone (compound 2.1) and 1,1,1-trifluoro-2-oxo-ethane [2- (1-Ethyl-propoxy) -5-nitro-phenyl] - [4- phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone (5-nitro-2- (oxetan-3-yloxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and toluene-4-sulfonic acid oxetan-3- (CAS: 26272-83-3) 452.4 [2- (3-Hydroxy-propoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and bromopropanol . 454.6 88. [2- (bicyclo [2.2.1] hept-2-yloxy) -5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5- nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and exo-2-bromonorbornane 490.589 [2- (2-methoxyethoxy) -5- (4-trifluoromethyl-phenyl) -piperrazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) ) -piperazin-1-yl) -methanone (compound 2.1) and 2-bromoethylmethyl ester 454.5%. [2- (3,3-dimethyl-butoxy) -5-nitrophenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro- phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1-bromo-3,3-dimethylbutane 480.81 91 [2- (1-ethoxy-cyclopropoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl ) -piperazin-1-yl-methanone (compound 2.1) and 1-bromo-1-ethoxy-cyclopropane 480.6 92 [2- (2-chloroethoxy) -5-nitro-phenyl] - [ 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (4-nitro-2- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -phenoxy} -acetonitrile (2-hydroxy-5-nitro) phenyl) -piperazin-1-yl] -methanone (compound 2.1) and brumoacetonitrile 435.494 5-nitro-2- (3,3,3-trifluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 1,1,1-trifluoro-1-iodopropane 492.4, nitro-2- (tetrahydro-pyran-4-yloxy) -phenyl] -14- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 2.1) and 4-chloro-tetrahydropyran 460.4 96 [2- (2,2-difluoro-ethoxy) -5- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin- 1-yl] -methanone (compound 2.1) and 1-bromo-2,2-difluoroethane 460.5 97 [2- (1,1,2,3,3,3-hexafluoro-propoxy) -5-nitro-phenyl ] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-Hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1- yl] -methanone (compound 2.1) and 3-hexafluoropropane 5.46.3

Exemplo 98Example 98

Preparação de {2-difluorametoxi-5-nitro-fenil) - [4- (4-tri-fluorometilfenil)-piperazin-l-il]-metanonaPreparation of {2-difluoromethoxy-5-nitro-phenyl) - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone

Em analogia com· um processo publicado na patente· de invenção WO 9749710, agitou-se a. 65 °C, ' durante 16 horas, uma solução de (2-hidroxi-5-nitrofenil)-.[4-(4-trifluoro-metíl-fenil)-piperazin-l-il]-metanona.(50 mg), carbonato de potássio (1 eq. ) e cloròfluoroacetato de etilo (1 eq.), no seio de DMF (1 mL) . Depois deste tempo, concentrou-se a mistura reaccional in vacuo e purificou-se por cromatografia. em coluna (Si02) , para se obter o composto do titulo (26 mg). EM &lt;m/e): 446, 0. (M+H+, 100%).In analogy to a process published in WO 9749710, A solution of (2-hydroxy-5-nitrophenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (50 mg) was added dropwise at 65 ° C for 16 hours. potassium carbonate (1 eq.) and ethyl chlorofluoroacetate (1 eq.) in DMF (1 mL). After this time, the reaction mixture was concentrated in vacuo and purified by chromatography. (SiO2) to give the title compound (26 mg). MS (m / e): 446.0 (M + H +, 100%).

Exemplo 99Example 99

Preparação de 5-nitro-2-(2,2,3,3-tetrafluoro-ciclobutil-metoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanonaPreparation of 5-nitro-2- (2,2,3,3-tetrafluoro-cyclobutylmethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone

Preparou-se o exemplo 99 em analogia com o exemplo 66, utilizando 1-(clorometil)-2,2,3,3-tetrafluorociclobutano [356-80-9]. EM (m/e): 536,3 (M+H+, 100 %) . 63Example 99 was prepared in analogy to example 66 using 1- (chloromethyl) -2,2,3,3-tetrafluorocyclobutane [356-80-9]. MS (m / e): 536.3 (M + H +, 100%). 63

Exemplo 100Example 100

Preparação de ES-nitro-2-[2,2,3,3,3-pentafluoro-propoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona A uma solução à temperatura de refluxo de 50 mg de (2-hidroxi-5-nitro-fehil} - [4- (4-trifluorometilfen.il} -piperazin-l-il]-metanona, no seio de acetona ,('2. mL) contendo carbonato de potássio (35 mg), adicionou-se trifluorome-tano-sulfonato de 2,2,3,3,3-pentafluoropropilo (54 mg), durante 10 minutos.. Fez-se o refluxo da, mistura reaccional durante 20 horas, antes de se concentrar in vacuo e purificar por cromatografia em coluna (SÍO2, ' CH^C^/MeOH) , para' se obter o composto do título, sob a forma de um sólido incolor (66 mg). EM (m/e): 569,0- (M+H+, 100 %} .Preparation of ES-nitro-2- [2,2,3,3,3-pentafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone To a solution of (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone in acetone (2 ml) was refluxed for 2 hours at reflux temperature of 50 mg of (2-hydroxy-5-nitro- containing potassium carbonate (35 mg), 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) was added over 10 minutes. The reaction mixture was refluxed for 20 minutes. (SiO 2, CH 2 Cl 2 / MeOH) to give the title compound as a colorless solid (66 mg). / e): 569.0- (M + H +, 100%).

Exemplo 101Example 101

Preparação de [2-[2-fluoro-l-fluorometil-etoxi)-5-nitro-fenil]-[4-(4 trifluorometil-fenil)-piperazin-l-il] -metanonaPreparation of [2- [2-fluoro-1-fluoromethyl-ethoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone

Fez-se o refluxo, durante a noite, de uma solução de (2-hidroxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), trifenilfosfina (76 mg) e di-isopropilazodi- carboxílato (48 mg), concentrou-se in vacuo e purificou-se por cromatografia em coluna (S1Ò2) , para se obter o composto do título, sob a forma de um sólido incolor (68 mg). EM (m/e): 474,1 (M+H+, 100 %) .'A solution of (2-hydroxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (50 mg) was refluxed overnight, 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine (76 mg) and diisopropylazodicarboxylate (48 mg) was concentrated in vacuo and purified by column chromatography (S1.2) to give the title compound as a colorless solid (68 mg). MS (m / e): 474.1 (M + H +, 100%).

Em analogia com o exemplo 48, prepararam-se os compostos 102 a 104 do quadro que se segue, a partir de (2-iodo-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (composto 1.9) e um álcool: 64In analogy to example 48, compounds 102 to 104 of the following table were prepared from (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazine -1-yl] -methanone (compound 1.9) and an alcohol: 64

Exemp. M° . Nome Sistemático Materiais Iniciais PM encont. (MH+) 102 [2-(1-etil-propoxi)-5- matano-sulfonil-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona (2-iodO“5-metano-sulfonil-fenil)-[4-(4-trifluoro-metil-fenil)-piperazin-l-il]-metanona (composto 1.9) e 3-pentanol 499,5 103 [5-metano-sulfonil-2-(3-metil-oxetan-3-ilmetoxi)-fenil]—[4-(4-trifluoro-metil-fenil) ~piperazin-l-il]-metanona (2-iodo-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metil-fenil)-piperazin-l-il]-metanona (composto 1.9) e metiloxetanometanol 513,4 104 rac-[2-(1-ciclqpropil-etoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluoro-metil-fenil)-piperazin-1-. il]-met'anona (2-iodo-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metil-fenil)-piperazin-l-il]-metanona (composto i.9) e rac-1-ciclopropil-etanol 497,4Exemp. M °. Systematic Name Initial Materials PM found. (MH +) 102 [2- (1-ethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-iodo- methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 1.9) and 3-pentanol 499.5 (5-methanesulfonyl- 3-ylmethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-iodo-5-methanesulfonyl-phenyl) - [ 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 1.9) and methyloxyethanemethanol 513.4 104 rac- [2- (1-Cyclopropyl-ethoxy) -5-methanesulfonyl-phenyl ] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-one. yl] methanone (2-iodo-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound i.9) and rac- 1-cyclopropyl-ethanol 497.4

Exemplo 2.3Example 2.3

Preparação de (2-fluOro-5-metano-sulfonil-fen.il) - [4- (5-tri-fluorometil-piridin-2-il)-piperaziri-l-il]-metanonaPreparation of (2-Fluoro-5-methanesulfonylphenyl) - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone

Preparou-se o composto 2.3 em analogia com o exemplo 5. utilizando o ácido 2-fluoro-5-(metilsulfonil)benzóico [247569-56-8] . e 1-(5-trifluorometil-2-piridil)-piperazina [132834-58-3].. EM '(m/e): 432,4 (M+H+, 100 %) .Compound 2.3 was prepared in analogy to example 5 using 2-fluoro-5- (methylsulfonyl) benzoic acid [247569-56-8]. and 1- (5-trifluoromethyl-2-pyridyl) -piperazine [132834-58-3]. MS (m / e): 432.4 (M + H +, 100%).

Exemplo 105Example 105

Preparação de [5-metano-sul£onil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-fenil]-[4-(5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanonaPreparation of [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazine yl] -methanone

Aqueceu-se a 150 °C,- durante 30 minutos e depois a 180 °C, durante 1 hora, num forno de micro-ondas, uma solução de de (2-fluoro-5-metano-sulfonil-fenil)-[4-(5-trifluorome-til-piridin-2-il)-piperazin—l-il]-metanona (composto 2.3) 65 (20 mg), 2-trifluorometil-2-propanol (0,053 mL) , carbonato de potássio ou carbonato de césio (3 equivalentes), no seio de dimetilacetamida. Depois deste tempo, concentrou-se a mistura reaccional e purificou-se por cromatografia em coluna (SiC&gt;2), para se obter o composto do título, sob a forma de um sólido amarelo claro (4,9 mg). EM (m/e): 540,3 (M+H+, 100 %) .A solution of (2-fluoro-5-methanesulfonyl-phenyl) -4- (4-methoxyphenyl) -1- - (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone (compound 2.3) 65 (20 mg), 2-trifluoromethyl-2-propanol (0.053 ml), potassium carbonate or carbonate of cesium (3 equivalents) in dimethylacetamide. After this time the reaction mixture was concentrated and purified by column chromatography (SiC &gt; 2) to give the title compound as a light yellow solid (4.9 mg). MS (m / e): 540.3 (M + H +, 100%).

Exemplo 2.4Example 2.4

Preparação de (2-isopropoxi-5-metano-sUlfonil-fen.il) -pipe-razin-l-il-metanona do ácido trifluoro-açéticoPreparation of trifluoroacetic acid (2-isopropoxy-5-methanesulfonyl-phenyl) -piperazin-1-yl-methanone

Agitou-se à temperatura ambiente, durante '2 horas, um a solução, do ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2, 1,0 g), 1-piperazinocarboxilato de terc- butilo (0,78 g) , TBTU. (1,4 g) e N-etildi-isopropilamina (4 mL). Depois desse tempo, concentrou-se a mistura reaccional in vácuo e purificou-se por cromatograf ia em coluna (Si02) ,. para se obter o éster terc-butilico do ácido 4-(2-.isopropoxi-5-metano-sulfonil-benzoil)-piperazino-l-carboxi-lico, sob a forma de uma espuma incolor (1,6 g) . Este ultimo foi dissolvido no seio de diclorometano (11 mL) e tratou-se com ácido trifluoroacético (4,2 mL) , durante 30 minutos. Depois desse tempo, concentrou-se a mistura reaccional in vacuo, para se obter o composto do titulo .(1,6 g) , sob a forma de um óleo amarelo claro. EM (m/e):' 327, 1. (M+H+, 100 %) .The solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g) g), TBTU. (1.4 g) and N-ethyldiisopropylamine (4 mL). After that time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2). to give 4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluoroacetic acid (4.2 mL) for 30 minutes. After that time, the reaction mixture was concentrated in vacuo to give the title compound (1.6 g) as a light yellow oil. MS (m / e): 327.1 (M + H +, 100%).

Exemplo 2.5Example 2.5

Preparação de 4-cloro-6-trifluorometil-pirimidina 66Preparation of 4-chloro-6-trifluoromethyl-pyrimidine

Fez-se o refluxo de . 6-trifluorometil-pirimidin-4-ol ([1546-78-7], 5 g) , no seio de oxicloreto fosforoso (17 mL) , durante 2 horas.. Concentrou-se cuidadosamente a mistura reaccional in vacuo e destilou-se o resíduo (Kugelrohr) a pressão reduzida (pb = 30-55 °C 0 10 mbar), para se obter o composto do título ([37 552-81-1], 1,4 g). EM (EI) : 182,0 (M) .The refluxing of. 6-trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was dissolved in phosphorus oxychloride (17 ml) for 2 hours. The reaction mixture was carefully concentrated in vacuo and distilled the residue (Kugelrohr) under reduced pressure (bp = 30-55øC 0-10 mbar), to provide the title compound ([37 552-81-1], 1.4 g). MS (EI): 182.0 (M).

Exemplo 106Example 106

Preparação de (2-isopropoxi-5-metano-sulfoiiil-fenil) - [4- (5-nitro-piridin-2-il)-piperazin-l-il]-metanonaPreparation of (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (5-nitro-pyridin-2-yl) -piperazin-1-yl] -methanone

Agitou-se a .120 °C, durante 20 horas, uma solução do ácido trifluoroacético de (2-isopropoxi-5-metano-sulfonil-fenil)-piperazin-1-il-metanona (composto 2.4, 80 mg), 2- cloro-5-nitro-piridina (29 mg), carbonato de potássio (50 mg) , no seio de 1-butanol (3 mL) . Depois desse tempo, concentrou-se a solução in vacuo e purificou-se por cromatografia era coluna (S1O2) , para se obter o composto do título, sob a forma de uma espuma branca (81 mg). EM (m/e): 449,1 (M-H+, 100 %) .A solution of (2-isopropoxy-5-methanesulfonyl-phenyl) -piperazin-1-yl-methanone trifluoroacetic acid (compound 2.4, 80 mg), 2- chloro-5-nitro-pyridine (29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL). After that time, the solution was concentrated in vacuo and purified by column chromatography (SiO2) to provide the title compound as a white foam (81 mg). MS (m / e): 449.1 (M-H +, 100%).

Exemplo 107Example 107

Preparação de {2-isopropoxi“5-metano-sulfonil-£enil)-[4-(6-trifluorometil-pirimidin-4-il)-piperazin-l-il]-metanonaPreparation of {2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyrimidin-4-yl) -piperazin-1-yl] -methanone

Preparou-se o exemplo 107 em analogia com o exemplo 106, utilizando 4-cloro-6-trifluorometil-pirimidina [37552-81-1]. EM (m/e): 473, 1 (M+H+, 100'%').Example 107 was prepared in analogy to example 106 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m / e): 473.1 (M + H +, 100%).

Exemplo 2.6 67Example 2.6 67

Preparação do ácido 2-(4-fluorofenoxi)-5-nifcrobenzóico 0 ácido 2-(4-fluoro-fenoxi)-5-nitro-benzóico pode ser preparado por um processo similar ao descrito na literatura (por exemplo, patente de invenção' WO 9938845) , por reacção do éster etílico do ácido. 2-cloro-5-nitro-benzóico [16588-17-3] com 4-fluoro-fenol [371-35-7], obtendo-se o éster etílico do ácido 2-(4-fluoro-fenõxi)-5-nitro-benzóico. 0 éster etílico do ácido 2-(4-fluoro-fenoxi)-5-nitro-benzóico pode ser hidrolisado por hidróxido de sódio, por exemplo, para se obter o composto do título. EM (m/e): 276,1 (M+H+, 100 %) .Preparation of 2- (4-fluorophenoxy) -5-nitrobenzoic acid 2- (4-Fluoro-phenoxy) -5-nitro-benzoic acid can be prepared by a procedure similar to that described in the literature (for example, WO 9938845), by reaction of the acid ethyl ester. 2-chloro-5-nitro-benzoic acid [16588-17-3] with 4-fluoro-phenol [371-35-7] to provide 2- (4-fluoro-phenoxy) -5- nitro-benzoic acid. 2- (4-Fluoro-phenoxy) -5-nitro-benzoic acid ethyl ester can be hydrolyzed by sodium hydroxide, for example to give the title compound. MS (m / e): 276.1 (M + H +, 100%).

Exemplo 2.7Example 2.7

Preparação do ácido 2 fS-difluoro^-piperazin-l-il-benzoni-tr i1o-trifluoro-acético (a) Éster terc-butlíico do ácido 4-(4-ciano-2,3-difluoro-fenil)-piperazino-l-carboxílico A uma solução de N-Boc-piperazina. (0,65 .g), no seio de DMA (20 mL), adicionou-se, lentamente, uma solução de. 2,3,4-trifluorobenzonitrilo (0,49 g) , no seio de DMA (10 mL) . Agitou-se a mistura reacçional durante 2 horas, a 80 °C. Depois desse tempo, eliminou-se o dissolvente in vacuo e purificou-se por cromatografia em coluna (Si02) , para se obter o composto do título, sob a forma de um sólido branco (0,76 g). (b) Ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-tri-flucro-acético 68 A uma solução de éster terc-butílico do ácido 4 — (4— cj.an.o-2,3-difluoro-fenil) -piperazino-l-carboxílico (0,72 g) , no seio de diclorometano (5 mL), adicionou-se ácido trifluoroacético e agitou-se a mistura reacciônal à temperatura ambiente, durante 30 minutos. Depois desse tempo, concentrou-se a mistura reacciônal in vacuo, para se obter o composto do título (0,63 g) . EM (m/e) : 224,3 25 (M+H+, 100 %) .(A) 4- (4-Cyano-2,3-difluoro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester 1-carboxylic acid To a solution of N-Boc-piperazine. (0.65 g.) In DMA (20 mL) was slowly added a solution of. 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80 ° C. After that time, the solvent was removed in vacuo and purified by column chromatography (SiO2) to provide the title compound as a white solid (0.76 g). (b) 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid To a solution of 4- (4-amino-2,3- (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid and the reaction mixture was stirred at room temperature for 30 minutes. After that time, the reaction mixture was concentrated in vacuo to give the title compound (0.63 g). MS (m / e): 224.325 (M + H +, 100%).

Exemplo 2.8Example 2.8

Preparação do ácido 2,5-difluoro-4-piperazin-l-il-benzo-nitrilo-trifluoro-acéticoPreparation of 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

Preparou-se. o exemplo 2.8 em analogia com o exemplo 2.7, utilizando 2,4,5-trifluorobenzonitrilo. EM (m/e): 224,3 (M+H+, 100 %) .It was prepared. Example 2.8 in analogy to example 2.7 using 2,4,5-trifluorobenzonitrile. MS (m / e): 224.3 (M + H +, 100%).

Exemplo 2.9Example 2.9

Preparação do ácido 5-metilsulfamoil-2-trifluorometoxi“ benzóico (a) Ácido 5-clorosulfonil-2-trifluorometoxi-benzóicoPreparation of 5-methylsulfamoyl-2-trifluoromethoxybenzoic acid (a) 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid

Adicionou-se, em pequenos lotes, uma solução de ácido 2-trifluorometoxi-benzóico [1979-29-9] (1,0 g) a ácido cloro-sulfónico (3,2 mL) , a 0 °C. Depois de a adição estar completa, agitou-se a mistura reacciônal a 70 °C, durante 4 horas e depois deixou-se à temperatura ambiente, durante a noite e aqueceu-se a 75 ÚC, durante mais 3 horas.. Depois desse tempo, verteu-se, lentamente, a mistura reacciônal em gelo e filtrou-se então o precipitado, lavou-se com água e 69 secou-se, para se obter o composto do titulo, sob a forma de um sólido branco (1,2 g). EM (m/e): 303,3 (M-H, 100 %). (b) Ácido 5-metilsulfamoil-2-trifluorometoxi-benzóico A uma solução do ácido 5-clorosulfonil-2-trifluoro-metoxi-benzóico (0,15 g) , no seio de diclorometano (1,5 mL) , adicionou-se uma solução de metilamina, no seio de metanol (8 M, 0,31 mL) e agitou-se a mistura reaccional durante 2 minutos após o que a precipitação ficou completa. Concentrou-se então a mistura reaccional in vacuo e dissolveu-se o resíduo no seio de NaOH 1 N (2 mL) e extraiu-se com éter de dietilo. Acidificou-se então a fase aquosa utilizando uma solução do ácido clorídrico 3 N (2 mL) e extraiu-se a solução com diclorometano (2 x 10 mL) . Secaram-se as fases orgânicas combinadas com sulfato de sódio e concentrou-se in vacuo, para se obter o composto do título, sob a forma de um sólido branco (0,12 g). EM (m/e): 298,0 (M-H, 100 %).A solution of 2-trifluoromethoxy-benzoic acid [1979-29-9] (1.0 g) was added in small batches to chlorosulphonic acid (3.2 ml) at 0 ° C. After the addition was complete, the reaction mixture was stirred at 70 ° C for 4 hours and then left at room temperature overnight and warmed to 75 ° C for an additional 3 hours. After that time , the reaction mixture was slowly poured into ice, and the precipitate was then filtered, washed with water and dried to give the title compound as a white solid (1,2 g). MS (m / e): 303.3 (M-H, 100%). (b) 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid To a solution of 5-chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 mL) a solution of methylamine in methanol (8M, 0.31 mL) was added and the reaction mixture was stirred for 2 minutes after which the precipitation was complete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethyl ether. The aqueous phase was then acidified using 3N hydrochloric acid solution (2 mL) and the solution was extracted with dichloromethane (2 x 10 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid (0.12 g). MS (m / e): 298.0 (M-H, 100%).

Exemplo 2.10Example 2.10

Preparação do ácido 5-metano-sulfonil-2-(3,3,3-trifTuoro-propoxi)-benzóico (a) Éster metálico do ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzóicoPreparation of 5-Methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid

Agitou-se, à temperatura ambiente, durante 1 hora, uma solução de 5-(metano-sulfonil)-salicilato de metilo [101371-44-2] (50 mg), trifenilfosfina (65 mg) 3,3,3- trifluoro-l-propanol e azodicarboxílato de di-terc-butilo (55 mg) , no seio de THF (3 mL) . Concentrou-se então a mistura reaccional in vacuo, purificou-se por cromatografia 70 em coluna (S1O2} , para se obter o composto do titulo, sob a forma de um sólido branco (65 mg). EM (m/e) : 327,5 (M+H+, 100 %) . (b) Ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzóicoA solution of methyl 5- (methanesulfonyl) -salicylate [101371-44-2] (50 mg), triphenylphosphine (65 mg), 3,3,3-trifluoro -1-propanol and di-tert-butyl azodicarboxylate (55 mg) in THF (3 mL). The reaction mixture was then concentrated in vacuo, purified by flash column chromatography (SiO2) to provide the title compound as a white solid (65 mg). MS (m / e): 327 (5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid

Ao éster metálico do ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)“benzóico (620 mg), no seio de etanol, a 60 °C, adicionou-se uma solução de NaOH 1 N (3,8 mL) e agitou-se a mistura reaccional durante 15 minutos. Depois desse tempo, adicionou-se, lentamente, 3,8 mL de HC1 1 N à mistura reaccional e evaporou-se o etanol in vacuo. Lavou-se então ò precipitado com água várias vezes, para se obter o composto do titulo (497 mg). EM (m/e): 311,0 (M-H+, 100 %).To the methyl ester of 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) benzoic acid (620 mg) in ethanol at 60 ° C was added a solution of 1 N NaOH (3.8 mL) and the reaction mixture was stirred for 15 minutes. After that time, 3.8 mL of 1N HCl was slowly added to the reaction mixture and the ethanol evaporated in vacuo. The precipitate was then washed with water several times to give the title compound (497 mg). MS (m / e): 311.0 (M-H +, 100%).

Exemplo 2.11Example 2.11

Preparação do ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóicoPreparation of 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid

Preparou-se o composto 2.11 em analogia com o composto 2.10, utilizando tetra-hidro-2H-piran-4-ol. EM (m/e): 299,4 (M-H, 100 %).Compound 2.11 was prepared in analogy to compound 2.10 using tetrahydro-2H-pyran-4-ol. MS (m / e): 299.4 (M-H, 100%).

Exemplo 2.12Example 2.12

Preparação do ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóicoPreparation of 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid

Preparou-se o composto 2.12 em analogia com o composto 2.10, utilizando ciclobutil-metanol. EM (m/e): 299, 4 (M-H, 71 100 %) .Compound 2.12 was prepared in analogy to compound 2.10 using cyclobutyl methanol. MS (m / e): 299.4 (M-H, 71%).

Exemplo 2.13Example 2.13

Preparação do ácido 3,5-di£luoro-4-piperazin-l-il-benzo-nitrilo-trifluoro-acéticoPreparation of 3,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

Preparou-se o composto 2.13 em analogia com o composto 2.7, utilizando 3,4,5-trifluorobenzonitrilo. EM (m/e): 224.1 (M+H+, 100 %) .Compound 2.13 was prepared in analogy to compound 2.7 using 3,4,5-trifluorobenzonitrile. MS (m / e): 224.1 (M + H +, 100%).

Exemplo 2.14Example 2.14

Preparação do ácido 2,6-difluoro-4-piperazin-l-il-benzoni-trilo-trifluoro-acéticoPreparation of 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

Preparou-se o composto 2.14 em analogia com o composto 2.7, utilizando 2,4,6-trifluorobenzonitrilo. EM (m/e): 224.1 (M+H+, 100 %) .Compound 2.14 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile. MS (m / e): 224.1 (M + H +, 100%).

Exemplo 2.15Example 2.15

Preparação do ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (a) Ácido 5-sulflno-2-trifluorometoxi-benzóicoPreparation of 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (a) 5-Sulfur-2-trifluoromethoxy-benzoic acid

Adicionou-se, em porções, ácido 5-clorosulfonil-2-trifluorometoxi-benzóico (1,0 g, composto 2.9.a) a uma solução de sulfito de sódio (3,1 g) , no seio de 16 mL de água. Manteve-se a mistura reaccional em condições básicas por meio da adição da quantidade apropriada de NaOH a 20 % e agitou-se à temperatura ambiente, durante 45 minutos. Depois desse tempo, arrefeceu-se a mistura reaccional com um banho de gelo e depois acidificou-se por meio da adição de uma solução deH2SC&gt;4 a 20 % até se atingir um pH = 2. Extraiu-se então a solução várias vezes com éter de dietilo 72 as fases orgânicas e acetato de etilo. Secaram-se combinadas (sulfato de sódio) e concentrou-se in vácuo, para se obter o composto do titulo, sob a forma de um sólido branco (0,88 g). (b) Ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (1.0 g, compound 2.9.a) was added portionwise to a solution of sodium sulfite (3.1 g) in 16 ml of water. The reaction mixture was kept under basic conditions by addition of the appropriate amount of 20% NaOH and stirred at room temperature for 45 minutes. After that time, the reaction mixture was cooled with an ice bath and then acidified by the addition of 4 to 20% H2 SO4 solution until a pH = 2 was obtained. The solution was then extracted several times with diethyl ether to the organic phases and ethyl acetate. The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give the title compound as a white solid (0.88 g). (b) 5-Methanesulfonyl-2-trifluoromethoxy-benzoic acid

Ao ácido 5-sulfino-2-trifluorometoxi-benzóico (0,82 g) , no seio de DMF (5 mL), adicionou-se 1,3 g de carbonato de potássio· e agitou-se a mistura reaccional durante 5 minutos, antes de se adicionar iodeto de metilo (0,66 mL) . Agitou-se então a mistura reaccional à temperatura ambiente, durante 60 horas. Depois desse tempo, concentrou-se a mistura reaccional in vacuo e tratou-se o resíduo com NaOH 1 N (10 mL) e THF (4 mL). Agitou-se a mistura reaccional durante mais 2 horas, à temperatura ambiente. Depois desse tempo, acidificou-se a solução com uma solução de HCl concentrado. Eliminou-se então o THF in vacuo e isolou-se o precipitado por filtração e lavou-se várias vezes com água, para se obter o composto do título. EM (m/e) : 283,0 (M-H, 100 %) .To 5-sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes, before adding methyl iodide (0.66 mL). The reaction mixture was then stirred at room temperature for 60 hours. After that time, the reaction mixture was concentrated in vacuo and the residue treated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for an additional 2 hours at room temperature. After that time, the solution was acidified with a concentrated HCl solution. THF was then removed in vacuo and the precipitate was collected by filtration and washed several times with water to give the title compound. MS (m / e): 283.0 (M-H, 100%).

Exemplo 2.16Example 2.16

Preparação do ácido 2,4-difluoro-6-piperazin-l-il-benzo-nitrilo-tri£luoro-acéticoPreparation of 2,4-difluoro-6-piperazin-1-yl-benzonitrile-trifluoroacetic acid

Preparou-se o composto 2.16 em analogia com o composto 2.7, utilizando 2,4,6-trifluorobenzonitrilo. EM (m/e): 224,1 (M+H+, 100 .%) .Compound 2.16 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile. MS (m / e): 224.1 (M + H +, 100%).

Exemplo 2.17 73Example 2.17

Preparação do ácido 2-{2-fluoro-l-fluoroiaetil-etoxi)-5-metano-sulfonil-benzóicoPreparation of 2- {2-fluoro-1-fluoro-ethyl-ethoxy) -5-methanesulfonyl-benzoic acid

Preparou-se o composto 2.17 em analogia com o composto 2.10, utilizando 1,3-difluoro-2-propanol. EM (m/e): 293,1 (M-H, 100 %).Compound 2.17 was prepared in analogy to compound 2.10 using 1,3-difluoro-2-propanol. MS (m / e): 293.1 (M-H, 100%).

Exemplo 2.18Example 2.18

Preparação do ácido 5-metano-sulfonil-2-(2,2,3,3,3-penta-fluoro-propoxi)-benzóico (a) Éster metílico do ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzóicoPreparation of 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoropropoxy) benzoic acid (a) 5-Methanesulfonyl-2- (2,2,2- 3,3,3-pentafluoro-propoxy) -benzoic acid methyl ester

Agitou-se a 60 °C, durante 5 horas, uma solução de 5-(metano-sulfonil)salicilato de metilo [101371-44-2] (0,50 g), éster 2,2,3,3,3-pentafluoro-propilico do ácido trifluo-ro-metano-sulfónico, (0,67 g) e carbonato de potássio (0,60 g) , no seio de acetona. Concentrou-se então a mistura reaccional in vacuo e purificou-se por cromatografia em coluna (S1O2), para se obter o composto do titulo, sob a forma de um sólido branco (0,44 g). EM (m/e): 363,1 (M+H+, 100 %) . (b) Ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi) -benzóicoA solution of methyl 5- (methanesulfonyl) salicylate [101371-44-2] (0.50 g), 2,2,3,3,3-trifluorobenzoyl ester pentafluoro-propyl ester (0.67 g) and potassium carbonate (0.60 g) in acetone. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2) to provide the title compound as a white solid (0.44 g). MS (m / e): 363.1 (M + H +, 100%). (b) 5-Methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid

Ao éster metílico do ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzóico (414 mg), no seio de THF (5 mL) , adicionou-se uma solução de mono-hidrato de hidróxido de lítio (72 mg), no seio de água (5 mL) e agitou-se a mistura reaccional à temperatura ambiente, durante 1 hora. Depois desse tempo, adicionou-se 1,72 mL de uma solução aquosa do ácido clorídrico 1 N. Concentrou-se 74 então a mistura reaccional in vacuo e lavou-se então o precipitado resultante, várias vezes, com água, para se obter o composto do titulo, sob a forma de um sólido branco (367 mg). EM (m/e): 347,1 (M-H, 100 %).To 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid methyl ester (414 mg) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (72 mg) in water (5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. After that time, 1.72 mL of a 1N aqueous hydrochloric acid solution was added. The reaction mixture was then concentrated in vacuo and the resulting precipitate was then washed several times with water to give The title compound was obtained as a white solid (367 mg). MS (m / e): 347.1 (M-H, 100%).

Exemplo 2.19Example 2.19

Preparação do ácido 2-terc-butoxi-5-metano-sialfonil-ben-zóico (a) Éster metiiico do ácido 2-terc-butoxi-5-metano-sulfo-nil-benzóico A uma solução de 5-(metano-sulfonil)-salicilato de metilo [101371-44-2] (0,50 g) , no seio de tolueno (5 mL) , adicionou-se N,N-dimetilformamida-di-terc-butilacetal e agitou-se a mistura reaccional a 80 °C, durante 1 hora.Preparation of 2-tert-butoxy-5-methanesulfonyl-benzoic acid (a) 2-tert-butoxy-5-methanesulfonyl-benzoic acid methyl ester To a solution of 5- (methanesulfonyl- ) -salicylate [101371-44-2] (0.50 g) in toluene (5 mL) was added N, N-dimethylformamide-di-tert-butylacetal and the reaction mixture was stirred at 80 ° C for 1 hour.

Depois desse tempo, concentrou-se a mistura reaccional in vacuo e purificou-se por cromatografia em coluna, para se obter o composto do titulo, sob a forma de um óleo incolor. (258 mg). EM (m/e): 304,4 (M+NH4\ 100 %) . (b) Ácido 2-terc-butoxi-5&quot;metano-sulfonil-benzóicoAfter that time the reaction mixture was concentrated in vacuo and purified by column chromatography to give the title compound as a colorless oil. (258 mg). MS (m / e): 304.4 (M + NH4 +, 100%). (b) 2-tert-butoxy-5-methanesulfonyl-benzoic acid

Ao éster metiiico do ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (1,58 g), no seio de THF (25 mL), adicionou-se uma solução de mono-hidrato de hidróxido de litio (0,35 g), no seio de água (25 mL) e agitou-se a mistura reaccional à temperatura ambiente, durante 4 horas. Depois desse tempo, eliminou-se o THF'in vacuo e à solução aquosa remanescente adicionou-se 8 mL de uma solução de HC1 1 N o que levou à precipitação do composto. Filtrou-se o precipitado e lavou-se várias vezes com água, para se obter 75 o composto do titulo (1,00 g) sob a forma de um sólido branco. EM (m/e) : 289, 9 (M+NH4+) .To the 2-tert-butoxy-5-methanesulfonyl-benzoic acid methyl ester (1.58 g) in THF (25 mL) was added a solution of lithium hydroxide monohydrate 35 g) was dissolved in water (25 ml) and the reaction mixture was stirred at room temperature for 4 hours. After that time the THF was removed in vacuo and the remaining aqueous solution was added 8 mL of a 1N HCl solution which led to the precipitation of the compound. The precipitate was filtered and washed several times with water to give the title compound (1.00 g) as a white solid. MS (m / e): 289.9 (M + NH4 +).

Exemplo 2.20Example 2.20

Preparação do ácido trifluoro-acético de 1-{2,5-difluoro-4-metano-sulfonil-fenil)-piperazina (a) Ácido 2,4,5-Trifluoro-benzeno-sulfínicoPreparation of 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine trifluoro-acetic acid (a) 2,4,5-Trifluoro-benzenesulfonic acid

Adicionou-se, em porções, cloreto de 2,4,5-trifluoro-benzeno-sulfonilo ([220227-21-4], 2,5 g), a uma sulfito de sódio (10,3 g) , no seio de 50 mL de água. Manteve-se a mistura reaccional em condições básicas por meio da adição da . quantidade apropriada de NaOH a 20 % e agitou-se à temperatura ambiente, durante 1 hora. Adicionou-se metanol à mistura reaccional e agitou-se a mistura reaccional à temperatura ambiente, durante mais uma hora. Depois desse tempo, arrefeceu-se a mistura reaccional com um banho de gelo e depois acidificou-se por meio da adição de uma solução de H2SO4 a 20 % até se atingir pH 2. Extraiu-se então a solução aquosa várias vezes com éter de dietilo e acetato de etilo. Extraiu-se outra vez a solução aquosa com acetato de etilo, utilizando um aparelho de Kutscher-Steudel (extracção contínua). Secaram-se as fases orgânicas combinadas (sulfato de sódio) e concentrou-se in vácuo, para se obter o composto do título, sob a forma de um sólido branco (2,1 g). (b) 1,2,4-Trifluoro-5-metano-sulfonil-benzeno2,4,5-Trifluoro-benzenesulfonyl chloride ([220227-21-4], 2.5 g) was added portionwise to a sodium sulfite (10.3 g) in 50 mL of water. The reaction mixture was kept under basic conditions by the addition of. appropriate amount of 20% NaOH and stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and the reaction mixture was stirred at room temperature for an additional hour. After that time, the reaction mixture was cooled with an ice bath and then acidified by the addition of a 20% H 2 SO 4 solution until pH 2 was reached. The aqueous solution was then extracted several times with diethyl ether and ethyl acetate. The aqueous solution was back extracted with ethyl acetate using a Kutscher-Steudel apparatus (continuous extraction). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo to give the title compound as a white solid (2.1 g). (b) 1,2,4-Trifluoro-5-methanesulfonyl-benzene

Ao ácido 2,4,5-trifluoro-benzeno-sulfínico (2,0 g) , no seio de DMF (17 mL) , adicionou-se 4,3 g de carbonato de potássio e agitou-se a mistura reaccional durante 5 76 minutos, antes de se adicionar iodeto de metilo (2,2 mL) . Agitou-se então a mistura reaccional à temperatura ambiente, durante 60 horas. Depois desse tempo, verteu-se em água (30 mL) na mistura reaccional e extraiu-se a mistura reaccional, várias vezes, com éter de dietilo. Secaram-se as fases orgânicas combinadas com sulfato de sódio e destilou-se a mistura remanescente, para se obter o composto do titulo, sob a forma de um óleo amarelo claro (2,1 g) . (c) Ácido trifluoro-acético de 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazinaTo 2,4,5-trifluoro-benzenesulfonic acid (2.0 g) in DMF (17 mL) was added 4.3 g of potassium carbonate and the reaction mixture was stirred for 5 hours. minutes, before methyl iodide (2.2 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After that time, the reaction mixture was poured into water (30 mL) and the reaction mixture was extracted several times with diethyl ether. The combined organic phases were dried over sodium sulfate and the remaining mixture was distilled to give the title compound as a light yellow oil (2.1 g). (c) 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine trifluoro-acetic acid

Obteve-se o composto do titulo em analogia com o exemplo 2.7, utilizando 1,2,4-trifluoro-5-metano-sulfonil-benzeno. EM (m/e): 277,1 (M+H+) .The title compound was obtained in analogy to example 2.7, using 1,2,4-trifluoro-5-methanesulfonyl-benzene. MS (m / e): 277.1 (M + H +).

Exemplo 2.21Example 2.21

Preparação do ácido trifTuoro-acético de 1-(3,5-difluoro-4-metano-sulfonil-fenil)-piperazinaPreparation of 1- (3,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine trifluoroacetic acid

Preparou-se o composto 2.21 em analogia com o composto 2.20, utilizando cloreto de 2,4,6-trifluoro-benzeno-sulfo-nilo [172326-59-9]. EM (m/e): 277,1 (M+H+) .Compound 2.21 was prepared in analogy to compound 2.20 using 2,4,6-trifluoro-benzenesulfonyl chloride [172326-59-9]. MS (m / e): 277.1 (M + H +).

Exemplo 2.22Example 2.22

Preparação do ácido 5-metano-s-ulfonil-2-(2,2,3,3-tetrafluo-ro-propoxi)-benzóicoPreparation of 5-Methanesulphonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid

Preparou-se o composto 2.22 em analogia com o composto 2.18, utilizando triflato de 2,2,3,3-tetrafluoro-l-propilo. EM (m/e): 329,1 (M-H). 77Compound 2.22 was prepared in analogy to compound 2.18 using 2,2,3,3-tetrafluoro-1-propyl triflate. MS (m / e): 329.1 (M-H). 77

Exemplo 2.23Example 2.23

Preparação do ácido trifluoro-acético de 1-(2,6-difluoro-4-metano- sulfonil-f enil)-piperazinaPreparation of 1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine trifluoroacetic acid

Preparou-se o composto 2.23 em analogia com o composto 2.20, utilizando cloreto de 3,4, 5-trifluoro-benzeno-sulfonilo [351003-43-5]. EM (m/e) : 277,1 (M+H+) .Compound 2.23 was prepared in analogy to compound 2.20 using 3,4,5-trifluoro-benzenesulfonyl chloride [351003-43-5]. MS (m / e): 277.1 (M + H +).

Exemplo 2.24Example 2.24

Preparação do ácido trifluoro-acético de 4-piperazin-l-il-6-trifluorometi1-pirimidinaPreparation of 4-Piperazin-1-yl-6-trifluoromethyl-pyrimidine trifluoroacetic acid

Preparou-se o composto 2.24 em analogia com o composto 2.7, utilizando 4-cloro-6-trifluorometil-pirimidina [37552-81-1]. EM (m/e): 233,1 (M+H+) .Compound 2.24 was prepared in analogy to compound 2.7 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m / e): 233.1 (M + H +).

Exemplo 2.25Example 2.25

Preparação de 2-piperazin-l-il-5-trifluorometil-pirimidina (a) 2-(4-benzil-piperazin-l-il)-5-trifluorometíl-pirimi- dina A uma solução de cloreto de (3-dimetilamino-2- trifluorometil-alilideno)-dimetil-amónio ([176214-18-9], 0,60 g), no seio de acetonitrilo (10 mL) , adicionou-se cloridrato de 4-benzil-piperazino-l-carboxamidina {[7773— 69-5], 0,66 g) e trietilamina (0,87 mL) e agitou-se a mistura reaccional durante 3 horas, à temperatura ambiente. Depois desse tempo, concentrou-se a mistura reaccional in vacuo purifícou-se por cromatografia em coluna, para se 78 obter o composto do titulo, sob a forma de um sólido amarelo claro (0,79 g). EM (m/e): 323,4 (M+H+) . (b) 2-piperazin-l-il-5-trifluorometil-pirimidina A uma solução de 2-(4-benzil-piperazin-l-il)-5-triflu-orometil-pirimidina (0,63 g) , no seio de metanol, adicionou-se paládio C (Degussa E101N; 5 %) e aqueceu-se a mistura reaccional a 60 °C, em atmosfera de hidrogénio.Preparation of 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (a) 2- (4-Benzyl-piperazin-1-yl) -5-trifluoromethyl-pyrimidine To a solution of (3-dimethylamino- 2-trifluoromethyl-allylidene) -dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-benzylpiperazino-1-carboxamidine hydrochloride [ 7773-69-5], 0.66 g) and triethylamine (0.87 ml) and the reaction mixture was stirred for 3 hours at room temperature. After that time, the reaction mixture was concentrated in vacuo and purified by column chromatography to give the title compound as a light yellow solid (0.79 g). MS (m / e): 323.4 (M + H +). To a solution of 2- (4-benzyl-piperazin-1-yl) -5-trifluoromethyl-pyrimidine (0.63 g) in dichloromethane of methanol was added palladium C (Degussa E101N, 5%) and the reaction mixture was heated to 60 ° C under hydrogen.

Deixou-se então a mistura reaccional arrefecer para a temperatura ambiente., filtrou-se o catalisador e eliminou-se o dissolvente in vacuo, para se obter o composto do titulo, sob a forma de um sólido incolor (0,41 g) . EM (m/e): 233,1 (M+H+) .The reaction mixture was then allowed to cool to room temperature, the catalyst was filtered, and the solvent was removed in vacuo to give the title compound as a colorless solid (0.41 g). MS (m / e): 233.1 (M + H +).

Em analogia com o exemplo 5 prepararam-se os compostos 108 a 280 do quadro que se segue a partir dos derivados de ácido e dos derivados de piperazina:In analogy to example 5 compounds 108 to 280 of the following table were prepared from the acid derivatives and piperazine derivatives:

Exemp. N°. Nome Sistemático Materiais Iniciais EM encont. &lt;MH+) 108 [2-(4-fluoro-fenoxi)-5-nitro-fenil]-[4-Η-ίΓίϋΙυοΓοιηβ^Ι-ίθηίΙ) -piperazinl-il]-metanona 1-(4-trifluorometiÍ-fenil)piperazina e ácido 2—(4— fluorofenoxi)-5-nitrobenzóico (coirposto 2.6) 490,5 109 2,3-difluoro-4-[4-(2-i s opropoxi-5-met ano -sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 2-i sopropoxi-5-metano-sulfoni1-berizóico (composto 1.2) 464,3 110 2,5-difluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 464,1 111 3- [4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-N-metil-4- 2-fluoro-4-piperazin-l-il-beiizonitrilo (patente de invenção WO 9808835) e ácido 5- 487,1 79 trifluorometoxi-benzeno- sulfonamida metilsulfamoil-2-trifluorometoxi-benzóico (composto 2.9) 112 3-fluoro-4-{4-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi) -benzóico (composto 2.10) 500,3 113 4-{4-[5-metano-sulfonil-2-(3, 3,3-trifluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo 4-píperazin-l-il-benzonitrilo (comercial) e ácido 5-metano-sulfonil-2-(3,3,3-tnfluoro-propoxi)-benzóico (composto 2.10) 482,3 114 2-fluoro-4-{4-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi) -benzóico (composto 2.10) 500,3 115 [5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-fenil]-[4- (4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzóico (composto 2.10) 525,2 116 [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano- sulfonil-2-(3,3,3— trifluoro-propoxi)-fenil]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 5-metano-sUlfonil-2,3, 3-trifluoro-propoxi)-benzóico (composto 2.10} 543,3 1 ί 7 [4- (2-fluoro-4- trifluorometil-fenil) - piperazin-l-il]-[5-metano- sulfonil-2-(3,3,3- trifluoro-propoxi)-fenil]- metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1} e ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzóico (composto 2.10) 543,2 118 1-(3-fluoro-4-{4-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzoil]-piperazin-l-il·}-fenil)-etanona 1-(3—fluoro-4-piperazín-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzóico (composto 2.10) 517,3 119 [4 - i2-fluoro-4 -metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2- 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(3,3,3- 553,2 80 (3,3,3-trifluoro-propoxi)-fenil]-metanona trifluoro-propoxi)-benzóico (composto 2.10) 120 4-{4-[5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzoil]-piparazin-1-il}-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido 5-metano-sulfoníl-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 470,0 121 . 2-fluoro-4-44-[5-metano-sulfonil-2-(tetra-hidro-piran~4-iloxi)-benzoil]-piperazln-l-il}-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção W0 9808835) e ácido 5-metano-sulf onil-2- (tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 488,1 122 3-fluoro-4-{4-[5-metano-sulfonil-2- (tetra-hid.ro-piran-4-iloxi)-benzoil]-piperazin-l-il}-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 488,0 123 [5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-etanona 1-(4-trifluoromstil-fenil)-piperazina (comercial) e ácido 5-metano-stilfonil-2- (tetra-hidro-píran-4-iloxi)-benzóico (composto 2.11) 513,3 124 [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-fenil]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-perazina (composto 5.1) e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóico .(composto 2.11) 531,0 125 (4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulf onil-2~ (tetra-hidro-piranenil]-metanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 531,2 126 1-(3-fluoro-4-{4-[5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzoil]-piperazin-l-il}-fenil)-etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690} e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 505,1 127 [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(tetrahidro-piran-4-iloxi)-fenil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfoníl-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 541,3 128 2,3-difluoro-4-[4-(2- ácido 2,3-difluoro-4-piperazin-l- 478,1 81 metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 129 4- (4-(2-ciclopropilmetoxi- 5- metano-sulfonil-benzoil)-piperazin-l-il]-2,3- difluoro-benzonitrilo ácido triflluoro-acético de 2,3-difluoro-4-piperazin-l-il-benzonitrilo (composto 2.7} e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 476,3 130 2,3-difluoro-4-{4-(5-metano-sulfoníl-2-(tetra-hidro-piran-4-iloxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-íl-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 2.11) 506,4 131 4- [4-{2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,3-difluoro-benzonitrilo ácido trifluoroacético de 2,3-difluoro-4-piperazin-l-il-benzonitrilo (composto 2.7) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 490,5 132 2,5-difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,5-difluoro-4-piperazin-1-il-benzonitrilo-trifluoroacético (composto 2.8) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 478,4 133 4- [4-(2-ciclopropilmetoxi- 5- metano-sulfonil-benzoil)-piperazin-l-il]-2,5- difluoro-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 476,3 134 2,5-difluoro-4-{4-[5-metano-sulfonil-2-(tetra-hidro-piran-4-iloxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 5-metano-sulfonil-2-(tetra-hidro-piran-4r iloxi)-benzóico (composto 2.11) 506,4 135 4- [4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2, 5-difluoro-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluorò-acético (composto 2.8) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 490, 5 136 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 456, 6 82 137 4- [4- (2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-pipsrazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-±l-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 472, 3 138 4- [4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benz6ico (composto 2.12) 472,3 139 (2-ciclobutilmetoxi-5-metano-sulfonil-fenil)-[4-(4~trifluorometil-fenil)-piperazin-l-il]-metanona. 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2-ciclobutilmetoxi-5- metano-sulfonil-benzóico (composto 2.12) 497,3 140 (2-ciclobutilmetoxi-5-metano-sulfonil-fenil)-[4-(3-fluoro-4-trifluorometíl-fenil)-piperazin-l-il]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 515,4 141 (2-ciclobutilmetoxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 515,4 142 l-{4-[4-(2- ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-fenil}-etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-cic1obuti lmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 489,5 143 (2-cicl obut i litie toxi-5-metano-sulfonil- fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 525,3 144 2-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluorometil-benzonitrilo (composto 5.2) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 522.4 145 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2, 3- ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acé-tico (composto 2.7) e ácido 2- 490,5 83 difluoro-benzonitrilo ciclobutilmetoxi-5-metano-sulfo-nil-benzóico (composto 2.12) 146 4- [4- (2-ciclobutilmetoxi-5-metano-sulfon.il-benzoil)jj-piperazin-l-il]-2,5-difluoro-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 490,5 147 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3,5-difluoro-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 2-cic-l.obutilmetoxi-5-metano -sulfonil-benzóico (composto 2.12) 490,5 148 4- [4-(2-ciclobutilmetoxi-5-metano-sulfonil- benzoil)-piperazin-l-il]-2, 6-difluoro-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) 490,5 149 2,5-difluoro-4-{4- [5-metano-sulfonil-2-(2, 2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 504,0 150 2,3-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 504, 1 151 2,5-difluoro-4-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 490,0 152 4-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 454,3 153 2-fluoro-4-(4-(5-metano-sulfonil-2-trifluorometoxi-benzoil) -piperazin-l-il]-benzonitrilo 2-fluoro-4-piperazin-l-il-benzo-nitrilo (patente de invenção WO 9808835) e ácido 5-metano-sulfonil-2-trifluo rometoxi-benzóico (composto 2.15) 472,1 154 3-fluoro-4-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil) -piperazin-l-il]-benzonitrilo 3-fluoro-4-piperazin-l-il- benzonitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-trifluorometoxi- 472, 0 84 benzóico (composto 2.15) 155 (5-metano-sulfonil-2-trifluorometoxi-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il]-metanona 1-(4-trifluorometil-fenil) -piperazina (comercial) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 514,2 (M-FNH4+) 156 [4-(3-fluoro-4-trifluo-rómetil-fenil)-piperazin-1-il]-(5-metano-sulfonil-2-trifluorometoxi-fenil)-metanona 1-(3-fluoro-4-trifluorometil-fenil) -piperazina (composto 5.1) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 532,5 (M+NH/) 157 [4-(2-fluoro-4-trifluorometil-fenil)-metano-sulfonil-2-trifluorometoxi-fenll)-metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 5-metano-sulfonil-2-. trifluorometoxi-benzóico (composto 2.15) 515,3 158. 2,3-difluoro-4-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 5-metano-sulfonil-2-trífluorometoxi-benzóico (composto 2.15) 507,4 (M+NH4+) 159 3,5-difluoro-4-[4-(5- metano-sulfonil-2- trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 507,3 (M+NH4+) 160 2,6-difluoro-4-[4-(5-metano-sulfcmil-2-trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 507,4 (M+NH4+) 161 [4- (2-fluoro-4-meta.no-sulfonil-fenil)-piperazin-l-il ]-(5-metano-sulfonil-2-trifluorometoxi-fenil)-. metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 542,0 (M+NH4+) ί 62. 2-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil)-piperazin-l-il]-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluorometil-benzonitrilo (composto 5.2) e ácido 5-metano-sulfonil-2-trifluorometoxi-benzóico (composto 2.15) 539,2 (M+NH/) 163 3,5rdifluoro-4-[4-(2-isopropoxi-5-metano- ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético 464,1 . 85 sulfonil-benzoil)-piperazin-l-il]-benzonitrilo (composto 2.13) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (coiiposto 1.2) 164 3,5-difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 3, 5-difluoro-4-piperazin-l-il—benzonitrilo-trifluoro-acético (composto 2.13) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 478,0 . 165 4- [4-(2-ciclopropilmetoxi- 5- metano-sulfonil-benzoil)-piperazin-l-il]-3,5-difluoro-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoroacético (composto 2.13) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 476,1 166 3,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2 2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 5-metano-sulfonil—2-(2,2,2-trifluoro-etoxi)—benzóico (composto 1.5) 504,1 167 4- [4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3,5-diflúoro-benzonitrilo , ácido 3,5-difluoro-4-piperazin-l-il—benzonitrilo-trifluoro-acético (composto 2.13) e ácido 2-ciclopentiloxi-5- metano-sulfónil-benzóico (composto 1.6) 490,3 168 2,6-difluoro-4-[4-(2- lsopropoxi-5-metano- sulfonil-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 481,1 (M+NH/) 169 2,6-difluoro-4-[4-(2- ' isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,6-di£luoro-4-piperazin-l-il-benzonitirilo-trifluoroacético (composto 2.14) e ácido 2-isobutoxi-5-metano-sulfoni1-benzóico (composto 1.3) 495,0 (M+NH/) 170 4- [4-(2-ciclopropilmetoxi— 5- metano-sulfonil-benzoil)-piperazin-l-il]-2,6-difluoro-benzonitrilo ácido 2, 6-difluoro-4-piperazin-l-il—benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2-ciclopropilmetoxi-5-métano-sulfonil-benzóico (composto 1.4)’ 493,0 (M+NH/) 17.1 2,6-difl.uoro-4-{4- [5-metano-sulfonil-2-(2,2,2-trifluorp-etoxi)-benzoil]-piperazin-l-il}- ácido 2, 6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro- 521,3 (M+NH4+) 86 benzonitrilo etoxi)-benzóico (composto 1.5) 172 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,6-difluoro-benzonitrilo ácido 2,6-difluoro-4-piperazin- 1- il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2- ciclopentiloxi-5-metano-sulf onil-benzóico (composto 1.6.) 507,3 (m+nO 173 2,4-difluoro-6- [4-(2- -isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo ácido 2,4-difluoro-6-piperazin- 1- il-benzonitrilõ-tri'fluoro-acético (composto 2.16) e ácido 2- isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 581,4 (M+NH/) 174 2-fluoro-4-{4- [2-(2-fluoro-l-flúorometil-etoxi)-5-raetano-sulfonil-benzoil]-piperazin-l-il}-. . benzonitrilo 2-fluoro-4-piperazin-l-il-benzo-nitrilo (patente de invençáo WO 9808Θ35) e ácido 2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sul- 1 fonil-benzóico (composto 2.17) 482,3. 175 3-fluoro-4-{ 4-.[2- (2-fluoro-1-fluorometil-etoxi) -5-metano-sulfonil-benzoil] -piperazin-l-il} benzonitrilo 3-fluoro-4-piperazin-l-il-benzo-nitrilo (patente de invenção WO 9625414) e ácido 2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sul-fonil-benzóico (composto 2.17) 482,4 176 2,3-difluoro-4-{4-[2-(2-fluoro-l-fluorometil-etoxi) - 5 - me t. ano - sul f on.i 1 -benzoil] -piperazin-l-il}-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acé-tico (composto 2.7) e ácido 2—(2— fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2.17) 500,3 177 2,5-difluoro-4-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzoil ]-piperazin-l-il}-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acé-tico (composto 2.8) e ácido 2-(2--fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2.17) 500,3 178 3,5-difluoro-4-{4-[2-(2-fluoro-l-fluorometil-metano-sulfonil-benzoil]-piperazin-l-il}-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2.17) 500,3 179 2,6-di£luoro-4-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzoil] -piperazin-l-il}-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2-(2-fluoro-l-metano-sulfonil-benzóico (composto 2.17) 500,3 87 ISO 2-fluoro-4-{4~[5-metano-sulf onil-2- (2,2,3,3,3-pentafluoro-propoxi)-benzoil]-piperazin-l-il]-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-metano-sulfonil-2-(2,2,3,3, 3-pentafluoro-propoxi)-benzóioo (composto 2.18) 536,3 181 3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-r pentafluoro-propoxi)-benzoil]-piperazin-l-il}-. . benzonitrilo 3-fluoro 4-piperazin-l-il-benzonitrilo. (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-(2,2,3,3, 3-pentafluoro-propoxi)-benzóioo (composto 2.18) 536,3 182 (5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzóioo (Composto 2.18) 561,3 183 [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulf onil-2- (2 , 2 , 3 , 3, 3- pentafluoro-propoxi)- fenil]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafíuo.ro-propoxi) -benzóico (composto 2.18) 579,0 184 2,3-difluoro-4-[4-[5-m.etano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzoil]-piperazin-l-il]-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 5-metano-sulfonil-2-(2,2,3, 3, 3-pentafluoropropoxi)-benzóico (composto 2.18). 554,0 185 2,5-difluoro-4-{4—[5— metano-sulfonil-2-(2,2,3,3,3-pentafluoro-piperazin-l-il}-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzóico (composto 2.18) 554,0 186 3,5-difluorõ-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzoil]- ácido 3,5-difluoro-á-piperazin-l-il-benzonitrilo.-trifluoro-acé-tico (composto 2.13) e ácido 5-metano-sulfonil-2-(2,2,3,3,3- 554,0 88 piperazin-l-il}-benzonitrilo pentafluoro-propoxi)-benzóico (composto 2.18) 187 2,6-difluoro-4-{4-[5-metano-sulf onil-2- (2,2,3,3,3-pentafluoro—propoxi)-ben-zoil]-piperazin-l-il)-ben-zonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acé— tico (composto 2.14) e ácido 5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-benzóico (composto 2.18) 571,2 (M+NH/) 188 [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-fenil]-metanona 1- (2-fluoro-4-metano-Sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2,2,3,3, 3-pentafluoro-propoxi)-benzóico (composto 2.18) 589,3 189 4-{4-[2-(2-fluoro-l-fluo-rometil-etoxi)-5-metano-sulf onil-benzoil] -piperazin-l-il}-benzonitrilo 4-piperazin-l-il-benzonitrilo (comércial) e ácido 2-(2-fluoro-1-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2,17) 4 64,1 ' 190 , . [2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-fenil]—[4—(4— trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 2-(2-fluoro-l-fluorometil-etoxi) -5-metano-sulfoniUoenzóico (composto 2.17) 507,3 19.1 [2-(2-fluoro-l-fluoro-me-til-etoxi)-5-metano-sulfo-nil-fenil]-[4-(3-fluoro-4-trifluorometil-feiiil) -piperazin-l-il]-metanona 1-(3-fluoro-4-trifluprometil-fenil)-piperazina (composto 5.1) e ácido 2-(2-fluoro-l-' fluorometil-etoxi)-5-metano-.sulfonil-benzóico (composto 2.17) 525,2 192 [2-(2-fluoro-l-fluoro-me-til-etoxi)-5-metano-sulfo-nil-fenil]-[4- (2-fluoro-4-trífluorometil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-trifluorometil-fe^ nil)-piperazina (composto 1.1) e ácido 2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2.17) 525,0 193 [2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-fenil]-[4-(2-flúoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1- (2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-(2-fluoro-l-fluorometil-etoxi) -5-metano-sulf onil.-benzóico (composto 2.17) 535,3 194 2-(4-[2-(2-fluoro-1-fluorometil-etoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluorome-til-benzonitrilo (composto 5.2) e ácido 2-(2-fluoro-l-fluoro-me-til-etoxi)-5-metano-sulfonil-etoxi)-5-metano-sulfonil-benzói-co (composto 2.17) 532,2 195 [4-(2,3-difluoro-4-metãno- 1-(2,3-difluoro-4-metano- 553,2 89 sulfonil-fenil)-piperazin-1-il]-[2-(2-fluoro-l-fluorometil-etoxi}-5-metano-sulfonil-fenil]-metanona sulfonil-fenil)-piperazina (composto 5.3) e ácido 2—(2— fluoro-l-fluorometil-etoxi)-5-metano-sulfonil-benzóico (composto 2.17) 196 4-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,3-difluoro-benzonitrilo ácido 2,3-dífluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 478,3 197 [4-(2,5-dÍfluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -(2-isopropoxi-5-(2-isopropoxi-5-metano- . sulfonilfenil)-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-tfifluoro-acético (composto 2.20) e ácido 2-isopropoxi-5-metano-sulfonil-benzôico (coirposto 1.2) 534,3 (M+NH,+) 196 [4-{3,5-difluoro-4-inetano-sulfonil-fenil)-piperazin-1-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona ácido 1-(3,5-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.21) é ácido 2-isopropoxi 5 metano-sulfonil-benzóico (composto 1.2) 534,3 (Μ+ΝΗ4+) 199 2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 2-piperazin-l-il-benzonitrilo (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóicò (composto 1.2) 428,5 .. 200 [ 4-.(2-f luoro-f enil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona ácido 1-(2-fluoro-fenil)-piperazina (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 421,3 201 [4-(4-cloro-fenil)-piperazin-l-il]-(2-, isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(4-cloro-fenil)-piperazina (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 437,3 ' 202 5-cloro-2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin—l-il]-benzonitrilo 5-cloro-2-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (corcposto 1.2) 462,1 203 [4-(4-Cloro-2-fluóro-fenil)-piperazin-l-il]-2-isopropoxi-5-inetano- . sulfonil-fenil)-metanona cloridrato de l-(4-cloro-2-fluorofenil)-piperazina (comercial) e ácido 2-isopropoxi'-5-metano-sulfonil-benzóico (composto 1.2) 455,4 204 [4-(4-cloro-3- 1 -(4-cloro-3-trifluorometil- 505,3 90 [ trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-suLfonil-fenil) -metanona fenil)-piperazina (comercial) .e ácido 2-isopropoxi-5-metano-sulfonil-benzóicò (composto 1.2) 205 [4-(3,4-dicloro-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(3,4-dicloro-fenil)-piperazina (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 471,0 . . 206 [4-(2-fluoro-4-metÍl-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1- (2-fluoro-4-metil-fenil) -piperazina (composto 5.4) e ácido 2- isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 435,3 207 rac-2,3-difluoro-4-4-(5-metano-sulfonil-2-(2,2,2-trifluoro-l-iaetil-etoxi) -benzoil]-piperazin-l-il}-benzonitrilo ácido 2,3-difluoro-4-piperazin-l-, il-benzonitrilo-trifluoro-acético (composto 2.7) e ácido rac-5-metano-sulfonil-2-(2,2,2-fcrifluoro-l-metil-etoxi)-benzóico (composto 3.1) 535,3 (M+NH4+) '208.' (2-i s opropoxi-5-met ano-sul f onil-f enil) -[4-(4-trif luororaetoxi-feni.l) -piperazin-l-il]-metanona 1-(4-trifluorometoxi-fenil)-piperazina (patente de invenção WO 03007954) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 487,3 203 2-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3, 3-tetrafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-metano-sulfonil-2-2,2,3,3-tetrafluoro-(propoxi)-benzóico (composto 2.22) 535,3 (M+NH4+) 210 3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo 3-fluoro-4 piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi) -benzóico (composto 2.22) 535,5 (M+NH4+) 211 [5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-benzóico (composto 2.22) 560,3 (M+NH4+) 212 [4-(2-fLuoro-4-trifluo-rometil-fenil)-piperazin-4-il]-[5-metano-sulfonil-2- 1- (2-f luoro-4-triflu.orometil-fenil)-pieperazina (composto 1.1) e ácido 5-metano-sulfonil-2- 578,2 (M+NH4+) 91 (2,2,3,3-tetrafluoro-propoxi) -fenil]-metanona (2,2,3,3-tetrafluoro-propoxi)-benzóico (composto 2.22) 213 2,3-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,3-difluoro-4-piperazin-1-il-benzonitrilo-trifluoro-acé-tico (composto 2.7) e ácido 5-metano-sulfonil-2- e 5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi) -benzóico (composto 2.22) 553,2 (M+NH„+) 214 2,5-difluoro-4-{4—[5— metãno-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 2,5-difluoro-4-pipera2in-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi) -benzóico (composto 2.22) 553,2 (M+NH4+) 215 3,5-difluoro-4-{4-[5-metano-sulfonil~2-(2,2,3,3-tetrafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-benzóico (composto 2.22) 553,0 (M+NH/) 216 2,6-difluoro-4-{4-[5- metano-sul£onil-2-(2,2,3,3-tetrafluoro-propoxi)-benzoil]-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acé-tico (composto 2.14) e ácido 5-metano-Sulfonil-2-(2,2,3,3-tetraf luoro-propoxi) -benzóico (composto 2.22) 553,2 (M+NH4+) 217 [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi) -fenil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina. (comercial) e ácido 5-metano-sulforiil-2-(2,2,3,3-tetrafluoro-propoxi)-benzóico (composto 2.22)' 588,3 (M+NH4+) 218 [4- (2,'6-difluoro-4-metano-sulfonil-il] -fenil) -piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona ácido 1-(2,6-difluoro-4-metano-súlfonil-fenil)- piperazino-tri-fluoro-acético (composto 2.23) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 517,3 213 3-cloro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil) -piperazin-l-il]-benzonitrilo 3-cloro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 4 62,3 220 [4-(2-cloro-4-nitro-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1- (2-cloro-4-nitro-fenil)- piperazina (patente de invenção EP 257864) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico 482,3 92 (composto 1.2) 221 3-{4-(2-isopropoxi-5-metano-sulfonil-benzoil)- piperazin-l-il]-benzonitrilo 3-piperazin-l-il-benzonitrilo (patente de invenção WO 02068399) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 428,4 222 [4-(3,5-dicloro-piridin-4-il)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(3,5-dicloro-piridin-4-il)-piperazina (comercial) e ácido 2- . isopropoxi-5-metano-sulfonil-benz ói co (composto 1.2) 474,0. 223 5-cloro-2-{4-[5-metano-sulfonil-2-¢2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo 5-cloro-2-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi) -benzóico (composto 1.5) 502,1 224 [4-(4-cloro-2-fluoro-Eenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona cloridrato de 1-(4-cloró-2-fluorofenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi) -benzóico (coirposto 1.5) 495,4 225 [4-(4-cloro-3-trifluo-rometil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1 -(4-cloro-3-trifluorometil-fenil)-piperazina (comercial) è ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 545,3 226 [4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.20) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 574,3 (M+NH4+) 227 [4-(2,6-difluoro-4-metano-sulfonil-fenii)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona ácido 1-(2,6-difluoro-4-metano-sulfonil^fenil)-piperazino-trifluoro-acético (composto 2.23) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 557,4 228 5-cloro-2- [4-(2-ciclopropilmetoxi-5-benzoil)-piperazin-l-il]-benzonitrilo 5-cloro-2-piperazin-l-il-benzo-nitrilo (patente de invenção WO 9625414) e ácido 2-ciclopropil-me toxi-5-me tano-sulfonil-benzóico (composto 1.4) 474,1 229 [4-(4-cloro-2-fluoro-fenil)-piperazin-l-il]- (2-ciclopropilmetoxi-5-metano- cloridrato de 1-(4-cloro-2-fluo-ro-fenil)-piperazina (comercial) e ácido 2-ciclopropilmetoxi-5- 467,3 93 sulfonil-fenil)-metanona metano-sulfonil-benzóico (composto 1.4) 230 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(3,4-dicloro-fenil)-piperazin-l-il]-metanona 1-(3,4-dicloro-fenil)-piperazina (comercial) e ácido 2-ciclopro-pilmetoxi-5-metano-sulfoni1-ben-zóico (composto 1.4) 483,3 231 [4-(4-cloro-3-trifluorometil-fenil)-piperazin-l-il]-(2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-metanona 1-(4-cloro-3-trifluorometil-fe-nil)-piperazina (comercial) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4} 517,0 232 (2-ciclopropilm®toxi-5-metano-sulfonil-fenil)-[4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-. 1-il]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-tri-fluoro-acético (composto 2.20) e ácido 2-ciclopropilmetoxi-5-me-tano-sulfonil-benzóicó (composto 1.4) 546,3 (Ml-NH/) 233 .· (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(2, 6-difluoro-4-metano-sulfonil-fenil}-piperazin-l-il] -metanona ácido 1-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazino-tri-fluoro-acético (composto 2.23) e ácido 2-ciclopropilmetoxi-5-me-tano-sulfoníl-benzóico (composto 1.4) 546,3 (M+NH4+) . 234 4-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,5-difluoro-benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido 2-terc-butoxl-5-metano-sulfonil-benzóico (composto 2.19) 478,1 235 4-[4-(2-t®rc-butoxi-5-metano-sulfonil-benzoíl)-. piperazin-l-il]-3,5-difluoro-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 478,1 236 4-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2,6-difluoro-benzonitrilo ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 478,1 237 (2-terc-butoxi-5-metano-sulfonil-fenil)'- [4- (2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil~ fenil)-piperazina (comercial) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 530,2 (M+NH4+) 238 2-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)- 2-piperazin-l-il-5- trifluorometil-benzonitrilo 527,3 (m+wh4+) 94 piperazin-l-il]-5-trifluorometil-benzonitrilo (composto 5.2) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 239 (2-terc-butoxi-5-metano-sulfonil-fen.il) - [4- (2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.3) e ácido 2-terç-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 548,3 (M+NH4+) 240 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -metanona 1-(3-cloro-5-trifluorometil-piridin-2-il)-piperazina (comercial) è ácido 2-terc-butoxi-5-metano-sulfoni1-benz 6i co (composto 2.19) 520,3 241 (2-1 e rc-butoxi-5-met ano-sulfonil-fenil)-[4-(5-cloro-piridin-2-il)-piperazin-l-il]-metanona 1-(5-cloro-piridin-2-il)-piperazina (patente de invenção W0 01062751) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19.) 452,3 242 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(5-trifluorometil-piridin-2-il)-piperazin-l-il]- metanona 1- ·[ 5-trif luorometil-piridin-2-il)-piperazina (comercial) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 486,4 243 4-[4-(2-terc-butoxí-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção W0 9808835) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 460,3 . 244 4-[4- (2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção W0 .9625414) e ácido 2-terc-butoxi-5-metano-sulfoni1-benzóico. (composto 2.19) 460,3 245 (2-terc-butoxi-5-metano-sulfonil-fenil) — [4 —(4 — trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 2-terc-butoxi-5-metano-sulfonil benzóico (composto 2.19) 485,5' 246 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(3-fluoro-4-trifluorometil- fenil)-piperazin-l-il]-metanona .1-(3-fluoro-4-trífluorometíl-fenil)-piperazina (composto 5.1) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 503,1 247 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil- 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-terc-butoxi-5-metano- 503,3 . 95 feníl)-piperazin-l-il]-metanona sulfonil-benzóico (composto 2.19) 248 6-[4-(2-terc-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-nicotinonitrilo 6-piperazin-l-il-nicotinonitrilo (comercial) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) '443,4 249 (2-terc-butoxi-5-metano-sulfonil-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.20) e ácido 2-terc-butoxi-5-metano-sulfonil-benzôico (composto 2.19) 548,3 (M+NH4+) 250 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(2,6-difluoro-4-metano-sulfonil-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona. ácido 1-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.23) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 548,3 (M+NH4+) 251 [4-(3, 4-d.icloro-fenil)-piperazin-l-il]-[5-metano-SUlfonil-2-(2,2,2-trifluòro-etoxi)-fenil]-. metanona l- (3,4-dicloro-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2- 2,2, 2-trifluoro-etoxi)-benzóico (composto 1.5) 511,0 252 2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-nicotinonitrilo 2-piperazin-l-il-nicòtinonitrilo (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 429,5 253 (2-isopropoxi-5-metano- sulfonil-fenil)-[4-4- trifluorometil-piperazin-1- il]- 2-piperazin-l-il-4-trifluorometil-pirimidina· (comercial) e ácido 2-isopropoxi-5-metàno-sulfonil-benzóico 473,0 254 rac-(4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-tri-fluoro-acético (composto 2.20) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1). 571 255 raç-[4-(2,6-difluoro-4-me-tano-sulfonil-fenil)-pipe-razin-l-il]-[5-metano-sul-fonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona ácido 1-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.23) e ácido rac-S-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 571,2 256 rac-5-cloro-2- /4-{5-meta-no-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-ben- 5-Cloro-2-piperazin-l-il-benzonitrilo (patente dê invenção WO 9625414) e ácido rac-5-metano- 516,2 96 1 zoil]-piperazin-l-il}-ben-zonitrilo sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -benzóico (composto 3.1) 257 rac-[4-(4-cloro-2-fluoro-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil]-metanona cloridrato de 1-(4-cloro-2-fluo-ro-fenil)-piperazina (comercial) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 509,3 258 rac-[4-(3,4-dicloro-fe-nil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metânona 1-(3,4-dicloro-fenil)-piperazina (comercial) e ácido rac-5-meta-no-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -benzóico (campos-to 3.1) .525,2 . 259 rac- [4-(4-cloro-3-trifluo-romet il-fenil)-piperazin-l-il]-[5-métano-sulfonil-2-{2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona 1-(4-cloro-3-trifluorometil-fe-nil)-piperazina (comercial) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 559,0 260 rac-3,5-difluoro-4-(4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil]-piperazin-l-il)-benzonitrilo ácido 3,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.13) e ácido rac-5-metano-sulfonil-2-(2,2,2-t ri fluoro-1-met i1-etoxi)-benzóico (composto 3.1) 518,2 261 rac-2,5-diflúoro-4-(4 —[5— (2,2,2-trifluoro-l-metil-etoxi) -benzoil] -piperazin-l-il] -benzonitrilo ácido 2,5-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido raç-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 518,0 262 râc-2,6-difluoro-4-(4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-2-(2,2,2-trifluoro-benzonitrilg ácido 2,6-difluoro-4-piperazin-l-il-benzonitrilo-trifluoro-acético (composto 2.14) e ácido rac-5-metano-sulfonil-(2,2,2-trifluoro-1-métil-etoxi)-benzóico (composto 3. D 517,8 263 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-pirimidin-2-il)-piperazin-l-il] -metanona 2-piperazin-l-il-4-trifluorometil-pirimidina (comercial) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 485,1 264 (2-i s opropoxi-5-me t ano-sulfonil-fenil)-[4-(2-trifluorometil-pirimidin-4-il)-piperazin-l-il]- ácido 4-piperazin-l-il-2-trifluorometil-pirimidino-trifluoro-acético (patente de invenção WO 030249) e ácido 2- 473,1 97 metanona isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 2 65 (2-terc-butoxi-5-metano-sulfonil-fenil)—[4—(3— fluoro-5-tri fluorometil-piridin-2-il)-piperazin-1-11]-metanona 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 504,0 266 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-4-trifluorometil-pirimidina . (comercial) e ácido 2-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 487,1 267 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(4- trifluorometil-pirimidin-2-11) -piperazin-l-il] -metanona 2-piperazin-l-il-4-trifluorometil-pirimldina (comercial) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 513,3 2 68 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi') -fenil]-[4-(4-trifluorometil^pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-4-trifluorometil-pirimidina (comercial) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 3.1) 527,0 269 (4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético e ácido 5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.6) 571,0 270 [4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-((R)-2,2,2-trifluoro-l-metil-etoxi) -fenil] -metanona ácido 1-(2, 5-difluoro-4-metano- sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.20) e ácido 5-metano-sulfonil-2-((R)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.7) 571,0 271 . [4-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-((S)-2,2,2-trifluoro-1-metil-etoxi)-fenil]-metanona ácido 1-(2, 6-diflnoro-4-!'metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.23) e ácido 5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.6) 571,2 272 [4-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2- ácido 1-(2,6-difluoro-4-metano-sulfonil-fenil)-piperazino-trifluoro-acético (composto 2.23) 571,2 98 ((R)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-raetanona e ácido 5-metano-sulfonil-2-((R)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.7) 273 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4- (2-trifluorométil-pirimidin-4-il)-piperazin-l-il]~ metanona ácido 4-piperazin-l-il-2-trifluorometil-pirimidino-trifluoro-acético (patente de invenção WO 030249) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 3.1) .527/0 274 rac- [5-metano-sul£onil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(6-rifluorometil-pirimidin-4-11)-piperazin-l-il]-metanona ácido 4-piperazin-l-il-6-trifluorometil-pirimidino-trifluoro-acético (composto 2.24). e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-,l^metil-etoxi) -benzóico (composto 3.1) 527,2 .275 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil]-.[4-(5-trifluorometil-pirímidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometil-pirimidina (composto 2.25) e ácido rac-5-metano-sulfonil-2-(2,2,2&quot; trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 527,2 276 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(5-trifluorometi1-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometil-pirimidina (composto 2.25) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 473,1 . 277 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil) -[4-(2-trif luor.ometil-pirimidin-4-il)-metanona ácido 4-piperazin-l-il-2-tr i fluoromet i1-pi r imidino-trifluoro-acético (patente de invenção WO 030249) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 485,1 278 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(6-trifluorometil-pirimidin-4-il)-piperazin-l-il] -metanona ácido 4-piperazin-l-il-6-t r i fluo rometil-pi rimidino-trifluoro-acético (composto 2.24) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-behzóico (composto 1.4) 485,5 279 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]—[4 —(2 — trifluorometil-pirimidin-4-| ácido 4-piperazin-l-il-2-trifluorometil-pirimidino-trifluoro-acético (patente de invenção WO 030249) e ácido 5- 513,3 99 il)-piperazin-l-il]-metanona metano-sulfoníl-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 280 [ 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(6- trifluorometil-pirimidin-4-il)-piperazin-l-il]-metanona ácido 4-piperazin-l-il-6-trifluorometil-pirimidino-trifluoro-acético (composto 2.24) e ácido. 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 513,3Exemp. No. Systematic Name Initial Materials EM Found. (4-fluoro-phenoxy) -5-nitro-phenyl] - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] piperazine and 2- (4-fluorophenoxy) -5-nitrobenzoic acid (co-compound 2. 6) 490.5 109 2,3-Difluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2,3- piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 2-isopropoxy-5-methanesulfonyl-pyrazoic acid (compound 1. 2) 464.3 110 2,5-difluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2,5-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 464.1 111 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4-2-fluoro-4-piperazin-1-yl] -butyronitrile ( WO 9808835) and 5-methyl-4-trifluoromethoxy-benzenesulfonamide (compound 2). 9) 3-Fluoro-4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro- piperazin-1-yl-benzonitrile (WO 9625414) and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 2. 10) 500.3 113 4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 4-piperazin-1-yl -benzonitrile (commercial) and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (Compound 2). 10) 482.3 114 2-fluoro-4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2-fluoro -4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 2. 10) 500.3 115 [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1 - (4-trifluoromethyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 2. 10) 525.2 116 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -phenyl] ] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 5-methanesulfonyl-2,3,3-trifluoro-propoxy) -benzoic acid (compound 2. 10 543.3 1 7 [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -phenyl] -methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1. 1 and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 2. 10) 543.2 118 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin-1-yl} phenyl) -ethanone (WO 9714690) and 5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -piperazine-1-carboxylic acid ) -benzoic acid (compound 2. 10) 517.3 119 [4- (2-Fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2-1- (2-fluoro-4-methanesulfonyl- -phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (3,3,3,5,5,2,2- (3,3,3-trifluoro-propoxy) -phenyl] -methanone trifluoro-propoxy) - benzoic acid (compound 2. 10) 4- {4- [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -benzonitrile 4-piperazin-1-yl-benzonitrile ( commercial) and 5-methanesulfonyl- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 470.0 121.  2-fluoro-4-4- [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2-fluoro-4-piperazin- yl-benzonitrile (WO 9808835) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 488.1 122 3-fluoro-4- {4- [5-methanesulfonyl-2- (tetrahyd. pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-methanesulfonyl- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 488.0 123 [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -ethanone 1 - (4-trifluoromethyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 513.3 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -phenyl] ] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -perazine (compound 5. 1) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid. (compound 2. 11) 531.0 125 (4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (tetrahydro-pyranenyl) -methanone 1- ( 2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1. 1) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 531.2 126 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -phenyl ) -ethanone (WO 9714690) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid benzoic acid (compound 2. 11) 505.1 127 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -phenyl] ] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 541.3 128 2,3-difluoro-4- [4- (2-2,3-difluoro-4-piperazin-1-yl) methanesulfonyl-benzoyl) -piperazin-1-yl] benzonitrile yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1. 3) 129 4- (4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile 2,3-difluoro-4-piperazinyl trifluoroacetic acid -1-yl-benzonitrile (compound 2. 7 and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 476.3 130 2,3-difluoro-4- {4- (5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2,3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 506.4 131 4- [4- (2-Cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile 2,3-difluoro- piperazin-1-yl-benzonitrile (compound 2. 7) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1. 6) 490.5 132 2,5-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2,5-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1. 3) 478.4 133 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,5-difluoro-benzonitrile 2,5-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 476.3 134 2,5-Difluoro-4- {4- [5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 5-methanesulfonyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 2. 11) 506.4 135 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,5-difluoro-benzonitrile 2,5-difluoro-4-piperazin- yl-benzonitrile-trifluoro-acetic acid (Compound 2). 8) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1. 6) 490.513 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile (commercial) and 2-cyclobutylmethoxy acid -5-methanesulfonyl-benzoic acid (compound 2. 12) 456.68 137 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -pipsrazin-1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin- -benzonitrile (WO 9808835) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 472,318 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 472.3 139 (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone.  1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 497.3 140 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (2-cyclobutylmethoxy-5-methanesulfonyl- 4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 515.4 141 (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro- 4-trifluoromethyl-phenyl) -piperazine (compound 1. 1) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 515.4 1- {4- [4- (2-Cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone 1- (3-fluoro- 4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 489.5 143 (2-Cyclutyl lithioxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1 - (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 525.3 144 2- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5-trifluoromethyl-benzonitrile 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5. 2) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 522. 4- [4- (2-Cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoro (Compound 2). 7) and 2-4,5,5-difluoro-benzonitrile cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (Compound 2. 12). 4- [4- (2-Cyclobutylmethoxy-5-methanesulfonyl) yl-benzoyl)] - piperazin-1-yl] -2,5-difluoro-benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 490.5 147 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3,5-difluoro-benzonitrile 3,5-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 2-cyclohexylcarbodiimide. 5-methanesulfonyl-benzoic acid (Compound 2). 12) 490.5 148 4- [4- (2-Cyclobutylmethoxy-5-methanesulfonylbenzoyl) piperazin-1-yl] -2,6-difluorobenzonitrile 2,6-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2. 12) 490.5 149 2,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 504.0 150 2,3-Difluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2,3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 504, 1115 2,5-Difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 2,5-difluoro-4-piperazin- 1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 490.0 152 4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile (commercial) and 5-methane sulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 454.3 2-fluoro-4- (4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 2-fluoro-4-piperazin-1-yl-benzo -nitrile (WO 9808835) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 472.1 3-fluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (Compound 2). 15) 155 (5-methanesulfonyl-2-trifluoromethoxy-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 514.2 (M-FNH 4 +) 156 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (5-methanesulfonyl-2-trifluoromethoxy-phenyl) -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 532.5 (M + NH /) 157 [4- (2-fluoro-4-trifluoromethyl-phenyl) -methanesulfonyl-2-trifluoromethoxy-phenyl) -methanone 1- (2-fluoro-4-trifluoromethyl- phenyl) -piperazine (compound 1. 1) and 5-methanesulfonyl-2-  trifluoromethoxy-benzoic acid (compound 2. 15) 515.3 158.  2,3-difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 2,3-difluoro-4-piperazin-1-yl-benzonitrile- trifluoro-acetic acid (compound 2. 7) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 507.4 (M + NH 4 +) 159 3,5-Difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 3,5-difluoro -4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 507.3 (M + NH 4 +) 160 2,6-difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile 2,6-difluoro acid -4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 507.4 (M + NH 4 +) 161 [4- (2-fluoro-4-meta. sulfonyl-phenyl) -piperazin-1-yl] - (5-methanesulfonyl-2-trifluoromethoxy-phenyl) -.  methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 542.0 (M + NH 4 +) δ 62.  2- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -5-trifluoromethyl-benzonitrile 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5. 2) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2. 15) 539.2 (M + NH) 163 3,5-difluoro-4- [4- (2-isopropoxy-5-methanoic acid 3,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid 464.1.  Sulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile (compound 2. 13) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Method 1). 2) 3,5-Difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 3,5-difluoro-4-piperazin-1-yl -Benzonitrile-trifluoroacetic acid (compound 2. 13) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1. 3) 478.0.   4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3,5-difluoro-benzonitrile 3,5-difluoro-4-piperazin-1-yl-benzonitrile trifluoroacetic acid (compound 2. 13) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 476.1 166 3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile , 5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 504.1 167 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3,5-difluoro-benzonitrile, 3,5-difluoro-4-piperazinecarboxylic acid -1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1. 6) 490.3 168 2,6-Difluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzonitrile 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid ( compound 2. 14) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 481.1 (M + NH) 169 2,6-difluoro-4- [4- (2'-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile acid 2,6 4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1. 3) 495.0 (M + NH 4) 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile 2,6- difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4): 493.0 (M + NH /) 17. 1 2,6-difl. 4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -2,6-difluoro-4-piperazin-1 -yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 5-methanesulfonyl-2- (2,2,2-trifluoro-521.3 (M + NH4 +) 86 benzonitrile ethoxy) -benzoic acid (compound 1. 5) 172 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile 2,6-difluoro-4-piperazin-1-yl -benzonitrile-trifluoroacetic acid (compound 2. 14) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1. 6. ) 507.3 2,4-Difluoro-6- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2,4- 6-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 16) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 581.4 (M + NH) 174 2-fluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl -.  .  2-fluoro-4-piperazin-1-yl-benzonitrile (WO 980835) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid ( compound 2. 17) 482.3.   175 3-fluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (Patent of Invention WO 9625414) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 482.4 176 2,3-Difluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methyl-  year - south f. 1-benzoyl] -piperazin-1-yl} -benzonitrile 2,3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 500.3 177 2,5-difluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 500.3 178 3,5-difluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile 3,5-difluoro acid -4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 500.3 179 2,6-difluoro-4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} - benzonitrile 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 2- (2-fluoro-1-methanesulfonyl-benzoic acid (compound 2. 17) 500.3 87 ISO 2-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl ] -benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid (compound 2. 18) 536.3 181 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -.  .  benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile.  (WO 9625414) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid (compound 2. 18) 536.3 182 (5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid (Compound 2. 18) 561.3 183 [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro -propoxy) -phenyl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluor. ro-propoxy) -benzoic acid (compound 2. 18) 579.0 184 2,3-Difluoro-4- [4- [5-m. 2,3-difluoro-4-piperazin-1-yl-benzonitrile-1-yl] -benzonitrile 2,3-Difluoro-4-piperazin- trifluoro-acetic acid (compound 2. 7) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoropropoxy) benzoic acid (compound 2. 18).  554.0 185 2,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-piperazin-1-yl} -benzonitrile 2,5- difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid (compound 2. 18) 554.0 186 3,5-Difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -3,5- difluoro-Î ± -piperazin-1-yl-benzonitrile. trifluoroacetic acid (compound 2. 13) and 5-methanesulfonyl-2- (2,2,3,3,3,5,5,4,0,8-piperazin-1-yl) -benzonitrile pentafluoro-propoxy) -benzoic acid (compound 2. 18) 187 2,6-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl ) -ben-zonitrile 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 5-methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoic acid (compound 2. 18) 571.2 (M + NH /) 188 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl- 3-methyl-3,3,3-pentafluoro-propoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl- 3,3,3-pentafluoro-propoxy) -benzoic acid (compound 2. 18) 589.3 189 4- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile 4-piperazin- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2.17) and 64.1%.  [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl- phenyl) -piperazine (commercial) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 507.3 19. 1 [2- (2-fluoro-1-fluoro-methyl-ethoxy) -5-methanesulfonyl-phenyl] - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin- yl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methano- sulfonyl-benzoic acid (compound 2. 17) 525.2 192 [2- (2-fluoro-1-fluoro-methyl-ethoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1. 1) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 525.0 193 [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1 -yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl- benzoic acid (compound 2. 17) 535.3 194 2- (4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -5-trifluoromethyl-benzonitrile 2-piperazin -1-yl-5-trifluoromethyl-benzonitrile (compound 5. 2) and 2- (2-fluoro-1-fluoro-methyl-ethoxy) -5-methanesulfonyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 532.2 195 [4- (2,3-Difluoro-4-methan-1- (2,3-difluoro-4-methano-5,5,2,2-sulfonyl-phenyl) -piperazin-1-yl] - [ 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-phenyl] -methanone sulfonyl-phenyl) -piperazine (compound 5. 3) and 2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoic acid (compound 2. 17) 196 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile 2,3-difluoro-4-piperazin-1 -yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 478.3 197 [4- (2,5-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5- (2-isopropoxy-5-methano-  sulfonylphenyl) -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-4-fluoro-acetic acid (compound 2. 20) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Compound 1. 1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -piperazin-1-yl] phenyl) -methanone 1- (3,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoro-acetic acid (compound 2. 21) is 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 534.3 (Μ + ΝΗ4 +) 199 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 2-piperazin-1-yl-benzonitrile (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 428.5. .  200 [4-. (2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (2-fluoro-phenyl) -piperazine 5-methanesulfonyl-benzoic acid (Compound 1). 2) 421.3 201 [4- (4-chloro-phenyl) -piperazin-1-yl] - (2-, isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-chloro-phenyl) - piperazine (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 1-yl] -benzonitrile 5-chloro-2-piperazin-1-yl-benzenesulfonamide, benzonitrile (WO 9625414) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Compound 1. 2) 462.1 203 [4- (4-Chloro-2-fluoro-phenyl) -piperazin-1-yl] -2-isopropoxy-5-inethane.  sulfonyl-phenyl) -methanone 1- (4-chloro-2-fluorophenyl) -piperazine hydrochloride (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 455.4 204 [4- (4-chloro-3-l- (4-chloro-3-trifluoromethyl-505.390 (trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5- methanesulfonyl-phenyl) -methanone (phenyl) -piperazine (commercial). and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (3,4-dichloro-phenyl) - piperazine (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 471.0.   .  [4- (2-fluoro-4-methyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (2-fluoro-4-methyl-phenyl ) -piperazine (compound 5. 4) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. (5-methanesulfonyl-2- (2,2,2-trifluoro-1-ethyl-ethoxy) -benzoyl] -piperazin-1- yl} -benzonitrile 2,3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and rac-5-methanesulfonyl-2- (2,2,2-trifluor-1-methyl-ethoxy) -benzoic acid (Compound 3. 1) 535.3 (M + NH 4 +) + 208. (2-iodopropoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethoxy-phenyl) 1-yl) -piperazin-1-yl] -methanone 1- (4-trifluoromethoxy-phenyl) -piperazine (WO 03007954) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 487.3 203 2-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2 4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methanesulfonyl-2-2,2,3,3-tetrafluoro- (propoxy) -benzoic acid (compound 2. 22) 535.3 (M + NH 4 +) 210 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] -piperazin- yl} -benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 535.5 (M + NH 4 +) 211 [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin- 1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 560.3 (M + NH 4 +) 212 [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-4-yl] - [5-methanesulfonyl-2- fluoro-4-trifluoromethyl- oromethyl-phenyl) -piperazine (compound 1. 1) and 5-methanesulfonyl-2-azabicyclo [2.2.0] octane-2-carboxylic acid (2,2,3,3-tetrafluoro-propoxy) -phenyl] -methanone (2,2,3,3-tetrafluoro- propoxy) -benzoic acid (compound 2. 22) 213 2,3-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile , 3-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 7) and 5-methanesulfonyl-2- and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 553.2 (M + NH +) 214 2,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] - piperazin-1-yl} -benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 553.2 (M + NH 4 +) 215 3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] -piperazin- yl} -benzonitrile 3,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 553.0 (M + NH /) 216 2,6-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) benzoyl] -benzonitrile 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 22) 553.2 (M + NH 4 +) 217 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,3- , 3-tetrafluoro-propoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine.  (commercial) and 5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoic acid (compound 2. 228) 588.3 (M + NH4 +) 218 [4- (2,6-Difluoro-4-methanesulfonyl-yl) -phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methane sulfonyl-phenyl) -methanone 1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (Compound 2). 23) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 517.3 213 3-chloro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 3-chloro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 4 62.3 220 [4- (2-chloro-4-nitro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (2-chloro -4-nitro-phenyl) -piperazine (EP 257864) and 2-isopropoxy-5-methanesulfonyl-benzoic acid 482.392 (compound 1. 2) 221 3- {4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 3-piperazin-1-yl-benzonitrile (WO 02068399) and 2- isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 428.4 222 [4- (3,5-dichloro-pyridin-4-yl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (3,5- 5-dichloro-pyridin-4-yl) -piperazine (commercial) and 2-  isopropoxy-5-methanesulfonyl-benzyl ester (Compound 1). 2) 474.0.   223 5-chloro-2- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 5-chloro-2-piperazin- 1-yl-benzonitrile (WO 9625414) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 502.1 224 [4- (4-chloro-2-fluoro-enyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] ] -methanone 1- (4-chloro-2-fluorophenyl) -piperazine hydrochloride (commercial) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (Compound 1). 5) 495.4 225 [4- (4-chloro-3-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (4-chloro-3-trifluoromethyl-phenyl) -piperazine (commercial) is 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 545.3 226 [4- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- ethoxy) -phenyl] -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoro-acetic acid (compound 2. 20) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 574.3 (M + NH 4 +) 227 [4- (2,6-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- , 2-trifluoro-ethoxy) -phenyl] -methanone 1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoro-acetic acid (compound 2. 23) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 557.4 228 5-chloro-2- [4- (2-cyclopropylmethoxy-5-benzoyl) -piperazin-1-yl] -benzonitrile 5-chloro-2-piperazin-1-yl-benzonitrile WO 9625414) and 2-cyclopropyl-methoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 474.1 229 1- (4-Chloro-2-fluoro-phenyl) -piperazin-1-yl] - (2-cyclopropylmethoxy-5- ro-phenyl) -piperazine (commercial) and 2-cyclopropylmethoxy-5-6,7,3-sulfonyl-phenyl) -methanone methanesulfonyl-benzoic acid (compound 1. 4) 230 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (3,4-dichloro-phenyl) -piperazin-1-yl] -methanone 1- (3,4-dichloro-phenyl) - piperazine (commercial) and 2-cyclopropyrimethoxy-5-methanesulfonyl-benzoic acid (Compound 1). 4-yl) - (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-chloro-3-trifluoromethyl-phenyl) 3-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2,5-difluoro-4-methanesulfonyl-phenyl) -piperazin-.  1-yl] -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2. 20) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 546.3 (M-NH) 233. · (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2,6-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2. 23) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 546.3 (M + NH 4 +).  4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,5-difluorobenzonitrile 2,5-difluoro-4-piperazin-1-yl -benzonitrile-trifluoroacetic acid (compound 2. 8) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 478.1 235 4- [4- (2-t-r-butoxy-5-methanesulfonyl-benzoyl) -.  piperazin-1-yl] -3,5-difluoro-benzonitrile 3,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 478.1 236 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile 2,6-difluoro- piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 478.1 237 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 530.2 (M + NH 4 +) 238 2- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -2-piperazin-1-yl-5-trifluoromethyl-benzonitrile 527.3 (m + wh4 +) piperazin-1-yl] -5-trifluoromethyl-benzonitrile (compound 5. 2) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 239 (2-tert-butoxy-5-methanesulfonyl-phen. yl) - [4- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2,3-Difluoro-4-methanesulfonyl-phenyl) -piperazine ( compound 5. 3) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 548.3 (M + NH 4 +) 240 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1- yl] -methanone 1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine (commercial) is 2-tert-butoxy-5-methanesulfonyl-benzylic acid (Compound 2). 19) 520.3 241 (2-1 and r-butoxy-5-methanesulfonyl-phenyl) - [4- (5-chloro-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (5-chloro-pyridin-2-yl) -piperazine (WO 01/062751) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19. ) 452.3 242 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] trifluoromethyl-pyridin-2-yl) -piperazine (commercial) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 486.4 243 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl benzonitrile (WO 9808835) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 460.3.   244 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile invention W0. 9625414) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid.  (compound 2. 19) 460.3 245 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl- (commercial) and 2-tert-butoxy-5-methanesulfonyl benzoic acid (Compound 2). 19) 485.5246 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone. 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5. 1) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 503.1 247 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine compound 1. 1) and 2-tert-butoxy-5-methano-503.3.  (Phenyl) -piperazin-1-yl] -methanone sulfonylbenzoic acid (compound 2. 19) 6- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -nicotinonitrile 6-piperazin-1-yl-nicotinonitrile (commercial) and 2- butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) '443.4 249 (2-tert-butoxy-5-methanesulfonyl-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2,5-difluoro-4-methane sulfonyl-phenyl) -piperazine-trifluoro-acetic acid (compound 2. 20) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 548.3 (M + NH 4 +) 250 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (2,6-difluoro-4-methanesulfonyl-4-methanesulfonyl-phenyl ) -piperazin-1-yl] -methanone.  1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoro-acetic acid (Compound 2. 23) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 548.3 (M + NH 4 +) 251 [4- (3,4-d. chloro-phenyl) -piperazin-1-yl] - [5-methano-sulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -.  methanone 1- (3,4-dichloro-phenyl) -piperazine (commercial) and 5-methanesulfonyl-2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 511.0 252 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -nicotinonitrile 2-piperazin-1-yl-nicotinonitrile (commercial) and 2-isopropoxy- -5-methanesulfonyl-benzoic acid (compound 1. 2) 429.5 253 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4-4-trifluoromethyl-piperazin-1-yl] -2-piperazin-1-yl-4-trifluoromethyl-pyrimidine ) and 2-isopropoxy-5-methanesulfonyl-benzoic acid 473.0 254 rac- (4- (2,5-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methane 2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoromethyl- acetic acid (compound 2. 20) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3. 1).  (4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro- 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2. 23) and rac-S-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3. 1) 571.2 256 rac-5-chloro-2- [4- (5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) Chloro-2-piperazin-1-yl-benzonitrile (WO 9625414 patent) and rac-5-methano-5,6,2,6-zoyl] -piperazin-1-yl} -benzonitrile sulfonyl-2- (2- , 2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3. 1) 257 rac- [4- (4-chloro-2-fluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy ) -phenyl] -methanone 1- (4-chloro-2-fluoro-phenyl) -piperazine hydrochloride (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1- methyl-ethoxy) -benzoic acid methyl ester (Compound 3). 1) 509.3 258 rac- [4- (3,4-dichloro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro- methyl-ethoxy) -phenyl] -methanone 1- (3,4-dichloro-phenyl) -piperazine (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro- methyl-ethoxy) -benzoic acid (3-methanesulfonyl-benzoic acid). 1) . 525.2.   259 rac- [4- (4-chloro-3-trifluoromethylphenyl) piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro- ethoxy) -phenyl] -methanone 1- (4-chloro-3-trifluoromethyl-phenyl) -piperazine (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro- methyl-ethoxy) -benzoic acid (Compound 3. 1) 559.0 Rac-3,5-difluoro-4- (4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1 -yl) -benzonitrile 3,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 13) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methoxyethoxy) benzoic acid (Compound 3. 1) 518.2 261 rac-2,5-difluoro-4- (4- [5- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl] -benzonitrile 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 8) and racemic 5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3. 1) 518.0 262 rc-2,6-difluoro-4- (4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1 -yl} -2- (2,2,2-trifluoro-benzonitrile) 2,6-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2. 14) and rac-5-methanesulfonyl- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3.  D 517.8 263 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin- 4-trifluoromethyl-pyrimidine (commercial) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1. 4) 485.1 264 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (2-trifluoromethyl-pyrimidin-4-yl) -piperazin-1-yl] 4-piperazin- 1-yl-2-trifluoromethyl-pyrimidine-trifluoroacetic acid (WO 030249) and 2-isopropoxy-5-methanesulfonyl-benzoic acid methanesulfonic acid (Compound 1). 2) 2- (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-11] -methanone 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5. 5) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 504.0 266 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin-1 4-trifluoromethyl-pyrimidine.  (commercial) and 2-butoxy-5-methanesulfonyl-benzoic acid (compound 2. 19) 487.1267 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (4-trifluoromethyl-pyrimidin-2-11) -piperazin-1-yl ] -methanone 2-piperazin-1-yl-4-trifluoromethyl-pyrimidine (commercial) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 513.3 2 68 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethyl-pyrimidin- 2-piperazin-1-yl-4-trifluoromethyl-pyrimidine (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1- methyl-ethoxy) -benzoic acid (Compound 3. 1) 527.0 269 (4- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S) 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid and 5-methanesulfonyl-2- (S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5. 6) 571.0 270 [4- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((R) 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2,5-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2. 20) and 5-methanesulfonyl-2 - ((R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5. 7) 571.0 271.  [4- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro- methyl-ethoxy) -phenyl] -methanone 1- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2. 23) and 5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5. 6) 571.2 272 [4- (2,6-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,6-difluoro- -4-methanesulfonyl-phenyl) -piperazine-trifluoro-acetic acid (compound 2. 23) 571.2 98 ((R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -raethanone and 5-methanesulfonyl-2 - ((R) -2,2,2- trifluoro-1-methyl-ethoxy) -benzoic acid methyl ester (Compound 5). 7) 273 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyrimidin-4-yl) -piperazin- 1-yl] -methanone 4-piperazin-1-yl-2-trifluoromethyl-pyrimidine-trifluoroacetic acid (WO 030249) and rac-5-methanesulfonyl-2- (2,2,2- trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3. 1) . 527/0274 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyrimidin-4-11) piperazin-1-yl] -methanone 4-Piperazin-1-yl-6-trifluoromethyl-pyrimidine-trifluoroacetic acid (compound 2. 24).  and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-, 1-methyl-ethoxy) -benzoic acid (compound 3. 1) 527.2. 275 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -. [4- (5-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (compound 2. 25) and rac-5-methanesulfonyl-2- (2,2,2 &quot; trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3. 1) 527.2 276 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (5-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin-1-yl -5-trifluoromethyl-pyrimidine (compound 2. 25) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1. 2) 473.1.  277 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2-trifluor. 4-piperazin-1-yl-2-trifluoromethylpyridine trifluoroacetic acid (WO 030249) and 2-cyclopropylmethoxy-5-methano- sulfonyl-benzoic acid (compound 1. 4) 485.1 278 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyrimidin-4-yl) -piperazin-1-yl] -methanone 4-piperazin- yl-6-trifluoromethyl-pyrimidine-trifluoro-acetic acid (Compound 2). 24) and 2-cyclopropylmethoxy-5-methanesulfonyl-behenzoic acid (compound 1. 4) 485.5 279 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyrimidin-4-yl) -piperazin- yl-2-trifluoromethyl-pyrimidine-trifluoro-acetic acid (WO 030249) and 5,53,399-yl) -piperazin-1-yl] -methanone methanesulfonyl-2- (2,2,2- trifluoro-ethoxy) -benzoic acid (compound 1. 5) [5-Methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyrimidin-4-yl) -piperazin-1-yl] -methanone 4-piperazin-1-yl-6-trifluoromethyl-pyrimidine-trifluoroacetic acid (compound 2. 24) and acid.  5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1. 5) 513.3

Em analogia com o exemplo 1.2 (b) , prepararam-se os compostos 3.1 a 3.5 do quadro &quot;que se segue, a partir do ácido 2-clorò-5-metano-sulfonil-benzóico e 'o álcool apropriado:In analogy to example 1.2 (b), the following compounds were prepared from 3-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:

Exemp. N°. Nome do Composto Álcool EM (m/e) 3.1 ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metíl-etoxi)-benzóico (Composto 3.1) rac-1,1,1-trifluoro-propan-2-cl 311,3 (MH&quot;) . 3.2 ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) cíclo-hexanol 297,3 (MH&quot;) 3.3 ácido 2-(2, 2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 2,2-dimetil-propan-l-ol 285,1 (MH&quot;) 3.4 ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) ciclobutanol 269,3 (MH&quot;) 3.5 ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) butan-2-ol 271,4 (MH&quot;)Exemp. No. Compound Name Alcohol EM (m / e) 3.1 rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3.1) rac-1,1,1 -profluoro-propan-2-ol 311.3 (MH &quot;). 3.2 2-Cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) cyclohexanol 297.3 (MH +) 3.3 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) cyclobutanol 269.3 (MH &quot;) 2,2-dimethylpropan- -2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound 3.5) butan-2-ol 271.4 (MH &quot;)

Em analogia com o exemplo 5,. prepararam-se os compostos 281 a 326 do quadro que se segue, a partir de derivados de ácido e derivados de piperazina.In analogy to example 5, Compounds 281 to 326 of the following table were prepared from acid derivatives and piperazine derivatives.

Exemp. N°. Nome Sistemático Materiais Iniciais m encont. (MH+) 281 1-[4- [4-(2-ciclo-hexiloxi-5-metano-sulfonil-benzoil)-piperazin-l-ilj_73_rf luoro-fenil}-etanona 1- (3-fluoro-4-piperazin-1-il-fe-nil)-etanona (patente de invenção WQ 9714690) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil- 503,5 100 ί benzóico (composto 3.2) 282 4-{4-(2-ciclo-hexiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 468,5 283 4-[4-(2-ciclo-hexiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-ciclo-hexiloxi-S-metano-sulfonil-benzóico (composto 3.2) 486,5 284 . 4-[4-(2-ciclohexiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 486,5 . 285 (2-ciclo-hexiloxi-5~metano-sulfonil-f en.il) - {4- (4-.trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 511,5 286 (2-ciclo-hexiloxi-5-[metano-sulfonil-fenil)-[4-(2-£luoro-4-trifluoro-metil-fenil)-piperazin-l-il] -metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 529,5 287 (2-ciclohexiloxi-5-metano-sulfonil-fenil)-[4-(3-flúoro-4-trifluoro-metil-fenil)-piperazin-l-il]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 2-ciçlo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 529,3 28 8 (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-(4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-' fenil)-piperazina (comercial) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 539,5 289 1- (4-H-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}-3-fluoro-fenil)-etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 491,5 290 4-[4-[2-(2,2-dimetil-propoxi)-5-metano-sulfo-nil-benzoil]-piperazin-l-il }-benzonitrilo 4-piperazin-l-il-benzonitrilo· (comercial) e ácido 2-(2,2-dimetil-propoxi)-5-metano-. sulfonil-benzdico (composto 3.3) 456, 6 291 4-{4-[2-(2,2-dimetil- 3-fluoro-4-piperazin-l-íl- 474,4 101 propoxi)-5-metano-sulfonil-benzoil)-piperazin-l-il}-3-fluoro-benzonitrilo benzonitrilo (patente de invenção WO 9625414) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 292 4-{4-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzoil]-piperazin-l-il}-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 474,5 293 [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) . 499,4 294 12-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]- [-4-(2-fluoro-4-trifluoro-metil-fenil)-piperazin-l-il] -metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 517,5 295 [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(3-fluoro-4-trifluoro-metil-fenil)-piperazin-l- il] -metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 517,5 296 [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-[4-(2-fluoro-fenil)-piperazina (comercial) e ácido 2-(2,2-dimetil-propoxi)-5-metano-sulfonil-benzóico (composto 3.3) 527,3 297 rac-1-(3-fluoro-4-{4T[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil)-piperazin-l-il}-fenil)-etanona 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 517,5 298 rac-4-{4-[5-metano-sulfo-nil-2- (2,2,2-trifluoro-l-metil-ètoxi)-benzoil]-pi-perázin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido rac-5-me-tano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzóico (composto 3.1) 500,4 299 rac-3-fluoro-4-{4-[5-meta-no-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil] -piperazin-l-il}- 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido rac-5-metano-sulfonil-2-etoxi)-benzóico 500,4 102. benzonitrilo (composto 3,1) 300 rac-2-fluoro-4-{4-[5-metano-sulfonil-2-{2,2,2-trifluoro-l-metil-etoxi) -benzoil]-piperazin-l-il·}- benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 500,4 301 rac-5-metano-sulfonil~2-(2,2,2-trifluoro-l-metil-etoxi)-fenil] — [4— {4— trifluorometil-fenil)-piperazin-l-il]-metanona 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 525,3 302 rac-[4-(2-fluoro-4-tri-fluorometil-fenil)-pipera-zin-l-il]-[5-metano-sulfo-nil-2-(2,2,2-trifluoro-1-metil-etoxi)-fenil]-metanona 1- (4-trif luorometil-f enil),-piperazina (composto 1.1) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 543,5 303 rac-[4-(3-fluoro-4-triflu-orometil-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-me-til- . etoxi)-fenil]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 543,5 304 rac- [4- (2-fluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido.rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 553,0 305 4—{4—[5-metano-sulfonil-2-(2-metòxi-etoxi)-benzoil]-piperazin-l-il]-benzonitrilo 4-piperaz in-1-i1-benzonit rilo (comercial) e ácido 5-metano^ sulfonil-2-(2-metoxi-etoxi)-benzóico (composto 1.10) 444,3 30 6 3-fluoro-4-{4-[5-metano-sulfonil-2-(2-metoxi-etoxi)-benzoil]-piperazin-1-il}-benzonitrilo 3-f1uoro-4-pipe ra z in-1-i1-benzo-nitrilo (patente de invenção WO 9625414) e ácido 5-metano-sulfo-nil-2-(2-metoxi-etoxi)-benzóico (composto 1.10) 462,5 307 2-fluoro-4-{4-[5-metano-sulfonil-2-(2-metoxi-etoxi }-benzo±l-piperazin-l-il]-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-metano-sulfonil-2-(2-metoxi-etoxi)-benzóico (composto 1.10) 462,5 308 (4-(2-fluoro-4- 1-(2-fluoro-4-trifluorometil- 505,5 103 trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2-metoxi-etoxi)-fenil]-metanona fenil)-piperazina (composto 1.1) e ácido 5-metano-sulfonil-2-(2-metoxi-etoxi)-benzóico (composto 1.10) 309 [4- (3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2-metoxi-etoxi)-fenil]-metanona 1-(3-fluoro-4-trifluorometil-fe-nil)-piperazina (composto 5.1) e ácido 5-metano-sulfonil-2-(2-me-toxi-etoxi)-benzóico (composto 1.10) 505,5 310 (4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-(5-metano-sulfonil-2-(2-metoxi-etoxi)-fenil]-metanona 1-(2—fluoro-4-metano-sulfónil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2-me-toxi-etoxi)-benzóico (composto 1.10) 515,5 311 l-{4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzoil}-piperazin-l-il]-3-fluoro-fenil}-etanona 1-(3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO . 9714690) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 475, 4 312 4- [4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-plperazin-1-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e 2-(comercial) e 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 440,5 313 4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-flucro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 458,5 314 4- [4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 458,5 315 (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil) -piperazina (comercial) e 2-ciclobutoxi-5-metano-sulfonil-bensóico acid metano-sulfonil-benzóico (composto 3.4) 483,5 316 (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-feníl)-piperazin-l-il}-metanona 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-ciclobutoxi-5-metano-sulfoníl-benzòico (composto 3.4) 501,5 . 317 (2-ciclobutoxi-5-metano-súlfonil-fenil)-[4-(3- 1-(3-fluoro-4-tri£luorometil-fenil)-piperazina (composto 5.1) 501,5 104 fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 318 (2-ciclobutoxi“5-metano-sulfonil-fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 511,5 319 rac-l“{4-[4~(2-sec-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-fenil}-etanona 1“(3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 477,4 ' 320 rac-4- [4- (2-sec-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo 4-piperazin-l-il-benzonitrilo (comercial) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 442,5 321 rac-4-[4-(2-sec-butoxi-5-metâno-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-il-benzonitrilô (patente de invenção W0 9625414) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 460,5 322 . rac-4-[4-(2-sec-butoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 460,5 323 rác-(2-sec-butoxi-5-metano-sulfonil-fenil)-[4- (4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil) -piperazina (comercial) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 485,5 324 rac-(2-sec-butoxi-5rl-(2-fluoro-4-metano-sulfon.il-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 503,3 325 rac-(2-sec-butoxi-5-metano-Sulfonil-fenil)-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido rac-2-sec-butoxi-5-metano-sulfonil-benzóico (composto 3.5) 503,3 326 rac-(2-sec-butoxi-5-meta-no-sulfonil-fenil)-[4-(2- 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e 513,5 105Exemp. No. Systematic Name Initial Materials m. (MH +) 1- [4- [4- (2-cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone 1- (3-fluoro-4-piperazin- 1-yl-phenyl) -ethanone (WO 9714690) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) cyclohexyloxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile (commercial) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) 468.5 283 4- [4- (2-cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl -benzonitrile (WO 9625414) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) 486.5 284. 4- [4- (2-Cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835 ) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) 486.5. 285 (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - {4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) - 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) 511.5 286 (2-cyclohexyloxy-5- [methanesulfonyl-phenyl) - [4- (2- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone (compound 1.1) and 2-cyclohexyloxy-5-methane (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5.1) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (compound 3.2) 529.3288 (2-cyclohexyloxy -5-methanesulfonyl-phenyl) - (4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl- ) -piperazine (commercial) and 2-cyclohexyloxy-5-methanesulfonylbenzoic acid (compound 3.2) 539.5 289 1- (4-H- [2- (2,4- Dimethyl-propoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -3-fluoro-phenyl) -ethanone 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 4- [4- [2- (2,2- 4-piperazin-1-yl-benzonitrile (commercial) and 2- (2,2-dimethyl-propoxy) -piperazin-1-yl} -benzonitrile 5-methano-. benzenesulfonic acid benzyl ester (compound 3.3) 456, 6191 4- {4- [2- (2,2-dimethyl-3-fluoro-4-piperazin-1-yl) -4,4,4-propoxy) -5-methanesulfonyl benzoyl) -piperazin-1-yl} -3-fluoro-benzonitrile benzonitrile (WO 9625414) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 4- {4- [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl and 2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 474.5 293 [2- (2,2-dimethyl-propoxy) -benzonitrile (WO 9808835) -5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2- 2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3). 499.4 294 12- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (3 4-trifluoromethyl-phenyl) -piperazine (compound 5.1) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) Dimethyl-propoxy) -5-methanesulfonyl-phenyl] -4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl- [4- 2-fluoro-phenyl) -piperazine (commercial) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 527.3297 rac-1- (3-fluoro-4- - {4 - [(5-Methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl) -piperazin-1-yl} -phenyl) -ethanone 1- (3-fluoro-4- piperazin-1-yl-phenyl) -ethanone (WO 9714690) and of rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) rac-4- {4- [5-methanesulfon- n-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile (commercial) and rac-5- (3-fluoro-4- {4- [5-fluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -3-fluoro-4-piperazin-1-yl-benzonitrile ( WO 9625414) and rac-5-methanesulfonyl-2-ethoxy) -benzoic acid 500.4 102. benzonitrile (compound 3.1) 300 rac-2-fluoro-4- {4- [5-methane -2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile (Patent of Invention WO 9808835) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 500.4301 rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) 1-yl) -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl- ethoxy) -benzoic acid (compound 3.1) 525.3 302 rac- [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- - (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and rac-5-methanesulfonyl-2- - (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 543.5 303 rac- [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl ] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl- ethoxy) -phenyl] -methanone 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5.1) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2- , 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and rac-5-methanesulfonyl- -2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 553.0 305 4- {4- [5-methanesulfonyl-2- (2-methoxyethoxy) - benzoyl] -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile (commercial) and 5-methanesulfonyl-2- (2-methoxyethoxy) -benzoic acid (compound 1.10) 3-fluoro-4- {4- [5-methanesulfonyl-2- (2-methoxy-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile 3-fluoro-4-piperazin- 5-methanesulfonyl-2- (2-methoxy-ethoxy) -benzoic acid (compound 1.10) 462.5 307 2-fluoro-4-methoxy-benzoic acid (WO 9625414) {4- [5-methanesulfonyl-2- (2-methoxy-ethoxy) -ben 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methanesulfonyl-2- (2-methoxy-ethoxy) -piperazin-1-yl) -benzonitrile benzoic acid (compound 1.10) 462.5 308 (4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methane (compound 1.1) and 5-methanesulfonyl-2- (2-methoxy-ethoxy) -benzoic acid (compound 1.10) 4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2-methoxy-ethoxy) -phenyl] -methanone 1- (3-fluoro-4- (compound 5.1) and 5-methanesulfonyl-2- (2-methoxyethoxy) benzoic acid (compound 1.10) 505.5 (4- (2-fluoro- 4-methanesulfonyl-phenyl) -piperazin-1-yl] - (5-methanesulfonyl-2- (2-methoxy-ethoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl- phenyl) -piperazine (commercial) and 5-methanesulfonyl-2- (2-methoxyethoxy) benzoic acid (compound 1.10) 515.5 311 1- {4- [4- (2-cyclobutoxy-5- -methanesulfonyl chloride 1-benzoyl} -piperazin-1-yl] -3-fluoro-phenyl} -ethanone 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 475, 4122 4- [4- (2-cyclobutoxy-5-methanesulfonyl-benzoyl) -placerazin-1-yl] -benzonitrile (Commercial) and 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 440.5 313 4- [4- (2-cyclobutoxy-5-methanesulfonyl- methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-cyclobutoxy-5-methanesulfonyl- benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl] -benzoic acid (compound 3.4) 458.5 314 4- [4- (2-cyclobutoxy-5-methanesulfonyl- 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 458.5 315 (2-cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (benzyloxy- 4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclobutoxy-5-methanesulfonyl-benzoic acid methanesulfonyl benzoic acid (compound 3.4 ) 4 83.5 316 (2-cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl} -methanone 1- (2-fluoro- trifluoromethyl-phenyl) -piperazine (compound 1.1) and 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 501.5. 317 (2-cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 5.1) 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 318 (2-cyclobutoxy) -5-methanesulfonyl-phenyl) - [4- (2-trifluoromethyl-phenyl) -piperazin- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone and commercially available 2-cyclobutoxy-5-methano- 1-yl] -3-fluoro-phenyl} -piperazin-1-yl) -piperazin-1-yl] (3-fluoro-4-piperazin-1-yl) -ethanone (WO 9714690) and rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound 3.5) , 4 'rac rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile 4-piperazin-1-yl-benzonitrile -2-sec-butoxy-5-methanesulfonylbenzoic acid (compound 3.5) 442.5 321 rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-b enzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and rac-2-sec-butoxy-5-methanesulfonyl benzoic acid (compound 3.5) 460.5 322. rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile 2-fluoro-4-piperazin-1-yl-benzonitrile of the compounds of the present invention) and rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound 3.5) 460.5323 rac- (2-sec-butoxy-5-methanesulfonyl-phenyl) - (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone and rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] 1-yl] -methanone (compound 1.1) and rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound 3.5) 503.3 325 (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (3-fluoro-4-trifluoromethyl- trifluoromethyl-phenyl) -piperazine (compound 5.1) and rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (compound 3.5) 503.3 326 rac- (2-sec-butoxy-5- -methanesulfonyl-phenyl) - [4- (2-l-2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 513.5

I fluoro-4-metano-sulfonil- ácido l-rac-2-sec-butoxi-5- fenil)-piperazin-il]- iuetano-sulfonil-benzóico metanona (composto 3.5)Fluoro-4-methanesulfonyl-1-rac-2-sec-butoxy-5-phenyl) -piperazin-1-yl] -ethanesulfonyl-benzoic acid methanone (Compound 3.5)

Exemplo 4.1Example 4.1

Preparação do ácido 6-etoxi-2-fluoro-3-metano-sulfonil-ben-zóico (a) Ácido 3-cloro-sulfonil-2,6-difluoro-benzóicoPreparation of 6-ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid (a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid

Agitou-se durante 2 horas, a 150 °C, 95 mmole.do ácido de 2,6-difluorobenzóico, no seio de 19 mL do ácido cloro-sulfónico. Verteu-se a mistura em 200 mL de um banho de gelo e agitou-se durante 20 minutos. Filtrou-se a pasta resultante, lavou-se com água e secou-se (20 °C durante a noite num excicador), para se obter o composto do titulo, sob a forma de um sólido incolor. EM (m/e).: 279,4 (MNa+, 81 %} ' . (b) Ácido 2,6-difluoro-3-sulfino-benzóico2,6-Difluorobenzoic acid in 95 ml of chlorosulfonic acid was stirred for 2 hours at 150 ° C. The mixture was poured into 200 mL of an ice bath and stirred for 20 minutes. The resulting slurry was filtered, washed with water and dried (20 ° C overnight in a desiccator) to provide the title compound as a colorless solid. MS (m / e): 279.4 (MNa +, 81%) (b) 2,6-Difluoro-3-sulfinobenzoic acid

Adicionou-se, lentamente, durante 20 minutos, 41 mmole de ácido . 3-cloro-sulfonil-2,6-difluoro-benzóico a uma solução de 310 mmole de sulfito de sódio, no seio de 200 mL de água. Agitou-se a mistura resultante durante 1 hora, à temperatura ambiente, arrefeceu-se para 0 °C e acidificou-se com ácido sulfúrico aquoso a 20 %. Extraiu-se o ácido sulfinico com acetato de etilo, secou-se sobre MgSCU e concentrou-se, para se obter o composto do titulo, sob a forma de.um sólido incolor. EM (m/e): 220,9 (M-H, 100 %) (c) Ácido 6-etoxi-2-fluoro-3-metano-sulfonil-benzóico 10641 mmol of acid was added slowly over 20 minutes. 3-chlorosulfonyl-2,6-difluoro-benzoic acid was added to a solution of 310 mmol of sodium sulfite in 200 mL of water. The resulting mixture was stirred for 1 hour at room temperature, cooled to 0 ° C and acidified with 20% aqueous sulfuric acid. The sulfinic acid was extracted with ethyl acetate, dried over MgSO4 and concentrated to give the title compound as a colorless solid. MS (m / e): 220.9 (M-H, 100%) (c) 6-Ethoxy-2-fluoro-3-methanesulfonyl benzoic acid 106

Tratou-se uma mistura de 27 mmole do ácido 2,6-difluoro-3-sulfino-benzóico e 9 mmole de Na2C03, no seio de 110 mL de metanol, com 72 mmole de iodeto de metilo. Agitou-se a mistura resultante durante a noite, a 60 °C, concentrou-se e dissolveu-se o residuo escuro no seio de 100 mL de etanol. Adicionou-se 100 mL de NaOH aquoso, 2 molar e fez-se o refluxo da mistura durante 2 horas. A concentração até cerca de 100 mL, fez precipitar um sólido amarelado que se filtrou e que se triturou com éter de dietilo, para se obter o composto do titulo impuro, que foi utilizado sem mais purificação.A mixture of 27 mmol of 2,6-difluoro-3-sulfinobenzoic acid and 9 mmol of Na2 CO3 in 110 mL of methanol was treated with 72 mmol of methyl iodide. The resulting mixture was stirred overnight at 60 ° C, concentrated and the dark residue dissolved in 100 mL of ethanol. Aqueous, 2 molar NaOH (100 mL) was added and the mixture was refluxed for 2 hours. Concentration to about 100 mL precipitated a yellowish solid which was filtered and triturated with diethyl ether to give the crude title compound which was used without further purification.

Exemplo 4.2Example 4.2

Preparação de 1-(4-tri£luorometano-sul£onil-fenil)-pipera-zinaPreparation of 1- (4-trifluoromethanesulfonyl-phenyl) -piperazine

Fez-se o refluxo, durante 2 horas, de uma mistura de 1 mmole de l-bromo-4-trifluorometano-sulfonil-benzeno [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 3 mmole de piperazina e 2 mmole de carbonato de potássio, no seio de 5 mL de acetonitrilo. Verteu-se a mistura resultante em água, extraiu-se com acetato de etilo, secoU-se, concentrou-se e purificou-se por cromatografia em coluna (SÍO2; Et20/ciclo-hexano), para se obter o composto do título, sob a forma de um sólido incolor. EM (m/e): 295,2 (MH+, 100 %)A mixture of 1 mmol of 1-bromo-4-trifluoromethanesulfonyl-benzene [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 3 mmol of piperazine and 2 mmol of potassium carbonate in 5 mL of acetonitrile. The resulting mixture was poured into water, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography (SiO 2: Et 2 O / cyclohexane) to give the title compound, as a colorless solid. MS (m / e): 295.2 (MH +, 100%)

Exemplo 4.3Example 4.3

Preparação do cloridrato de 1-(2,4-bis-trifluorometil-fe-nil)-piperazina (a) Éster terc-butílico do ácido 4-(2,4-bis-trifluorome-til-fenil)-piperazino-l-carboxilico 107Preparation of 1- (2,4-bis-trifluoromethyl-phenyl) -piperazine hydrochloride (a) 4- (2,4-Bis-trifluoromethyl-phenyl) -piperazin-1- -amide

Agitou-se a 80 °C, durante 3 horas, uma mistura de 5 mmole de 2,4-bis(trifluorometil)bromobenzeno, 6 mmole de N-BOC-piperazina, 8 mmole de NaOtBu, 0,5 mmole de rac-2,2'-bis(difenilfosfino)-1,1' -binâftilo e 1 mmole de um complexo de clorofórmio e tris-(dibenzilidenoacetona)dipaládio, no seio de 20 mL de tolueno. Diluiu-se então a mistura com água, extraiu-se com acetato de etilo, secou-se e purificou-se por cromatografia em coluna (Si02; ciclo-hexano/acetato de etilo a 9:1), para se obter o composto do titulo, sob a forma.de um óleo amarelado. EM (m/e) : 399,1 (MH\ 100 %) . (b) Cloridrato de 1-(2,4-bis-trifluorometil-fenil)-pipera-zinaA mixture of 5 mmol 2,4-bis (trifluoromethyl) bromobenzene, 6 mmol N-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmol rac-2 , 2'-bis (diphenylphosphino) -1,1'-binaphthyl and 1 mmol of a chloroform and tris (dibenzylideneacetone) dipalladium complex in 20 ml of toluene. The mixture was then diluted with water, extracted with ethyl acetate, dried, and purified by column chromatography (SiO2, 9: 1 cyclohexane / ethyl acetate) to give the title compound. in the form of a yellowish oil. MS (m / e): 399.1 (MH +, 100%). (b) 1- (2,4-Bis-trifluoromethyl-phenyl) -piperazine hydrochloride

Agitou-se 3 mmole do éster terc-butílico do ácido 4-(2,4-bis-trifluorometil-fenil)-piperazino-l-carboxilico, no seio de 10 mL de 1,4-dioxano, saturado com HC1 gasoso. Passadas 4 horas, à temperatura ambiente, evaporou-se a mistura reaccional até à secagem, para originar o composto do titulo, sob a forma de um sólido incolor. EM (m/e): 299,3 (MH\ 100 %)3-Methyl 4- (2,4-bis-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester was stirred in 10 mL of 1,4-dioxane, saturated with gaseous HCl. After 4 hours at ambient temperature, the reaction mixture was evaporated to dryness to give the title compound as a colorless solid. MS (m / e): 299.3 (MH +, 100%)

Exemplo 4.4Example 4.4

Preparação do cloridrato de l-[4-{5-metil-[l,2,4]oxadiazol-3-il)-fenil]-piperazina (a) Éster terc-butílico do ácido 4-[4-(5-metil-[1,2, 4]oxa-diazol-3-11)-fenil]-piperazino-l-carboxílicoPreparation of 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -piperazine hydrochloride (a) 4- [4- (5-methyl - [1,2,4] oxa-diazol-3-11) -phenyl] -piperazine-1-carboxylic acid

Aqueceu-se em atmosfera de árgon, a 90 °C, durante 17 horas, uma mistura bem agitada de 0,015 mmole de bis(tri-t-butilfosfino)paládio, 0,01 mmole de brometo de cetiltrime- 108 tilamónio, 2 mmole hidróxido de potássio em pó, 2 mmole de 3-(4-bromo-fenil)-5-metil-[1,2,4]oxadiazole e 2,1 mmole de N-BOC-piperazina, no seio de 1 mL tolueno. Diluiu-se a mistura reaccional resultante com água, extraiu-se com acetato de etilo e purificou-se o produto por cromatografia em coluna (SÍO2, ciclo-hexano/acetato de etilo a 7:3), para se obter o composto do título, sob a forma. de. um sólido amarelado. EM (m/e): 345,3 (MH+, 100 %) (b) Cloridrato de 1-[4-(5-metil-[1,2,4]oxadiazol-3-il)-fe-nil]-piperazinaA well stirred mixture of 0.015 mmol bis (tri-t-butylphosphino) palladium, 0.01 mmol cetyltrimethylammonium bromide, 2 mmol hydroxide was heated under argon at 90 ° C for 17 hours. of potassium powder, 2 mmol of 3- (4-bromo-phenyl) -5-methyl- [1,2,4] oxadiazole and 2.1 mmol of N-BOC-piperazine in 1 mL toluene. The resulting reaction mixture was diluted with water, extracted with ethyl acetate and the product purified by column chromatography (SiO 2, cyclohexane / ethyl acetate 7: 3) to afford the title compound , under the form. in. a yellowish solid. MS (m / e): 345.3 (MH +, 100%) (b) 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] - piperazine

Agitou-se 1 mmole do éster terc-butílico do ácido 4-. [4- (5-metil·^ [1,2,4] oxadiazol-3-il) -fenil] -piperazino-l-car-boxílico, no seio de 3 mL de 1,4-dioxano, saturado com HCl gasoso. Passadas 2 horas à temperatura ambiente, evaporou-se a mistura reaccional até à secagem, para se obter o composto do título, sob a forma de um sólido incolor. EM (m/e) : 245,1 (MH+, 100.%)1-Methyl ester was stirred 1 M. [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -piperazine-1-carboxylic acid, in 3 ml of 1,4-dioxane, saturated with gaseous HCl . After 2 hours at ambient temperature, the reaction mixture was evaporated to dryness to give the title compound as a colorless solid. MS (m / e): 245.1 (MH +, 100%)

Exemplo 4.5Example 4.5

Preparação de cloridrato de 1-(4-oxazol-2-il-fenil)-piperazina (a) 4-Bromo-N-(2,2-dimetoxi-etil)-benzamidaPreparation of 1- (4-oxazol-2-yl-phenyl) -piperazine hydrochloride (a) 4-Bromo-N- (2,2-dimethoxy-ethyl) -benzamide

Tratou-se uma solução de 24 mmole de dimetilacetal de aminoacetaldeído, dissolvido em 30 mL de água, com 25 mmole de hidrogeno-carbonato de potássio. Adicionou-se, lenta-mente, uma solução de 23 . mmole de cloreto de 4-bromobenzoílo, no seio de 50 mL de acetona, agitando-se durante um período de 30 minutos. Evaporou-se a acetona e extraiu-se a fase aquosa, 3 vezes, com acetato de etilo, 109 para se obter o composto do titulo impuro, sob a forma de um sólido ligeiramente castanho. EM (m/e): 287,1 (M-H, 43 %) (b) 2-(4-Bromo-fenil)-oxazoleA solution of 24 mmol of aminoacetaldehyde dimethylacetal dissolved in 30 mL of water was treated with 25 mmol of potassium hydrogen carbonate. A solution of 23 was slowly added. of 4-bromobenzoyl chloride in 50 ml of acetone was added dropwise over a period of 30 minutes. The acetone was evaporated and the aqueous phase was extracted 3 times with ethyl acetate, to give the crude title compound as a slightly brown solid. MS (m / e): 287.1 (M-H, 43%) (b) 2- (4-Bromo-phenyl) -oxazole

Tratou-se uma solução de 21 mmole de pentóxido fosforoso em 20 mL de ácido metil-sulfónico com 7 mmole de 4-bromo-N-(2,2-dimetoxi-etil)-benzamida. Aqueceu-se a mistura reaccional durante 5 horas, .a 130- °C.· Arrefeceu-se para a temperatura ambiente e verteu-se num banho de gelg. Filtrou-se o sólido' resultante e secou-se, para se obter o composto do titulo impuro, sob a forma de um sólido acastanhado. EM (m/e): 224,0 (MH', 24 %) (c) Éster terc-butílico do ácido 4-(4-oxazol-2-il-fenil)-piperazino-1-carboxilico ' Preparou-se em analogia com o exemplo 4.4 (a), a partir de 2-(4-bromo-fenil)-oxazole e N-BOC-piperazina. EM (m/e) : 330,3 (MH+, 100 %) . (d) Cloridrato dê 1-(4-oxazoÍ-2-il-fenil)-piperazinaA solution of 21 mmol of phosphorus pentoxide in 20 mL of methyl sulfonic acid was treated with 7 mmol of 4-bromo-N- (2,2-dimethoxy-ethyl) -benzamide. The reaction mixture was heated for 5 hours at 130 ° C. It was cooled to room temperature and poured into a gel-bath. The resulting solid was filtered and dried to give the crude title compound as a tan solid. MS (m / e): 224.0 (MH +, 24%) (c) 4- (4-Oxazol-2-yl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester analogy to example 4.4 (a), from 2- (4-bromo-phenyl) -oxazole and N-BOC-piperazine. MS (m / e): 330.3 (MH +, 100%). (d) 1- (4-Oxazol-2-yl-phenyl) -piperazine hydrochloride

Preparou-se em analogia com o exemplo 4.4 (b) , a partir . do éster terc-butílico do ácido 4-(4-oxazol-2-il-fenil)-piperazino-l-carboxílico e ácido clorídrico, no seio de dioxano. EM (m/e): 230,1 (MH+, 100 %)Prepared in analogy to example 4.4 (b), starting from of 4- (4-oxazol-2-yl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m / e): 230.1 (MH +, 100%)

Exemplo 4.6Example 4.6

Preparação do cloridrato de 1-[4-(5-metil-[1,3,4]oxadiazol-2-il)-fenil]-piperazina 110 (a) 2-(4-Bromo-fenil)-(1,3,4)oxadiazolePreparation of 1- [4- (5-methyl- [1,3,4] oxadiazol-2-yl) -phenyl] -piperazine hydrochloride 110 (a) 2- (4-Bromo-phenyl) - (1,3 , 4) oxadiazole

Dissolveu-se 12,3 mmole da hidrazida do ácido 4-bromo-benzóico no seio de 26 mL de ortoformato de trietilo. Agitou-se a mistura reaccional durante a noite, a 140 °C, evaporou-se e cristalizou-se o resíduo no seio de etanol, para se obter o composto do titulo, sob a forma de um sólido incolor. EM (m/e): 225,0 (MH+, 100 %) (b) Éster terc-butilico do ácido 4-(4-[1,3,4]oxádiazol-2-11-fenil)-piperazino-l-carboxílico12.3 mmol of 4-bromo-benzoic acid hydrazide was dissolved in 26 mL of triethyl orthoformate. The reaction mixture was stirred overnight at 140 ° C, evaporated and the residue crystallized from ethanol to give the title compound as a colorless solid. MS (m / e): 225.0 (MH +, 100%) (b) 4- (4- [1,3,4] Oxadiazol-2-11-phenyl) -piperazin- carboxylic acid

Preparou-se em analogia com o exemplo 4.4 (a), a partir de 2-(4-bromo-fenil)-[1,3,4]oxadiazole e N-BOC-pipe-razinat EM (m/e) : 342,2 (MH+, 100 %) (c) Cloridrato de 1-[4-(5-metil-[1,3,4]oxadiazol-2-il)-fe-nil]-piperazinaPrepared in analogy to example 4.4 (a) from 2- (4-bromo-phenyl) - [1,3,4] oxadiazole and N-BOC-piperazin-4-yl ester MS (m / e): 342 , 2 (MH +, 100%) (c) 1- [4- (5-methyl- [1,3,4] oxadiazol-2-yl) -phenyl] piperazine hydrochloride

Preparou-se em analogia com o exemplo 4.4 (b) , a partir do éster terc-butílico do ácido 4-(4-[1,3,4]oxa-diazol-2-il-fenil)-pipe.razino-l-carboxílico e ácido clorídrico, no seio de dioxano. EM (m/e): 245,3 (MH+, 100 %)Prepared in analogy to example 4.4 (b) from 4- (4- [1,3,4] oxa-diazol-2-yl-phenyl) -piperazin-1 carboxylic acid and hydrochloric acid in dioxane. MS (m / e): 245.3 (MH +, 100%)

Exemplo 4.7Example 4.7

Preparação do cloridra:to de 1-[4-(2-metil-2H-tetrazol-5-il)-fenil]-piperazina (a) 5-(4-Bromo-fenil)-2-metil-2H-tetrazolePreparation of 1- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -piperazine hydrochloride (a) 5- (4-Bromo-phenyl) -2-methyl-2H-tetrazole

Agitou-se à temperatura ambiente, durante 24 horas, uma mistura de 3,5 mmole de 5-(4-bromo-fenil)-2H-tetrazole, 0,2 mmole de brometo de tetrabutilo e amónio, 4,4 mmole de 111 iodeto de metilo, 6 mL de hidróxido de sódio aquoso 1 M e 6 mL de diclorometano. Diluiu-se a mistura reaccional com água e extraiu-se com acetato de etilo. Secou-se a fase orgânica, evaporou-se e purificou-se o produto por croma-tografia em coluna (SÍO2; ciclo-hexano/acetato de etilo a 7:3). EM (m/e) : 239,1 (MH+, 29 %) (b) Éster terc-butílico do ácido 4-[4-(2-metil-2H-tetra- zol-5-il)-fenil]-piperazino-l-carboxillco Preparóu-se em analogia com o exemplo 4.4 (a), a partir de 5-(4-bromo-fenil)-2-metil-2H-tetrazole e N-BOC-piperazina. EM (m/e): 345,1 (MH+, 41 %) (c) Cloridrato de 1-[4-(2-metil-2H-tetrazol-5-il)-fenil]- piperazinaA mixture of 3.5 mmol of 5- (4-bromo-phenyl) -2H-tetrazole, 0.2 mmol of tetrabutyl ammonium bromide and 4.4 mmol of 111 mmol) was stirred at room temperature for 24 hours. methyl iodide, 6 ml of 1 M aqueous sodium hydroxide and 6 ml of dichloromethane. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the product purified by column chromatography (SiO 2, 7: 3 cyclohexane / ethyl acetate). (B) 4- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -piperazine carboxylic acid Prepared in analogy to example 4.4 (a) from 5- (4-bromo-phenyl) -2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m / e): 345.1 (MH +, 41%) (c) 1- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -piperazine hydrochloride

Preparou-se em analogia com o exemplo 4.4 (b) , a partir do éster terc-butílico do ácido 4-[4-(2-metil-2H-tetrazol-5-il)-fenil]-piperazino-l-carboxílico e o ácido clorídrico, no seio de dioxano. EM (m/e): 245, 1 (MH+, 100 %)Prepared in analogy to example 4.4 (b) from 4- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m / e): 245.1 (MH +, 100%)

Exemplo 4.8Example 4.8

Preparação do cloridrato do éster metilico do ácido 3,4,5,6-tetra-hidro-2H-[1,2']bipirazinil-5'-carboxilico (a) Éster 5f-metilico do éster 4-terc-butílico do ácido 2,3,5,6-tetra-hidro-[1,2']bipirazinil-4,5'-dicarbo-xílicoPreparation of 3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-5'-carboxylic acid methyl ester hydrochloride (a) Amino-4-tert-butyl ester 2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4,5'-dicarboxylic acid

Aqueceu-se à temperature de refluxo, durante 3 horas, uma mistura de 17 mmole de metil-5-cloropirazino-2-carboxilato, 18 mmole de N-BOC-piperazina e 20 mmole de 112 K2C03, no seio de 20 mL de acetonitrilo. Concentrou-se a mistura reaccional, diluiu-se com água e extraiu-se com acetato de etilo. O composto do titulo recristalizou no seio de acetato de etilo, para se obter um sólido incolor. EM (m/e) : 323,4 (MH+, 100 %) (b) Cloridrato do éster metilico do ácido 3,4,5,6-tetra-hidro-2H-[1,2']bipirazinil-5'-carboxllicoA mixture of methyl 5-chloropyrazine-2-carboxylate (17 mmol), 18 mmol of N-BOC-piperazine and 20 mmol of 112 K 2 CO 3 in 20 mL of acetonitrile . The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to give a colorless solid. MS (m / e): 323.4 (MH +, 100%) (b) 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyrazinyl-5'- carboxylic acid

Preparou-se em analogia com o exemplo 4.4 (b), a partir do éster 5'-metilico do éster 4-terc-butilico do ácido 2,3,5,6-tetra-hidro-[1,2']bipirazinil-4,5'-dicarboxí-lico e 1,4-dioxano saturado com HC1 gasoso. EM (m/e): 223,1 (MH&quot;, 100 %)Prepared in analogy to example 4.4 (b) from 2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-tert-butyl ester 5'-methyl ester 5'- 4,5'-dicarboxylic acid and 1,4-dioxane saturated with gaseous HCl. MS (m / e): 223.1 (MH &quot;, 100%)

Exemplo 4.9Example 4.9

Preparação de trifluoroacetato de 6'-cloro-3,4,5,6-tetra-hidro-2H-[1,2']bipirazinilo (a) Éster terc-butilico do ácido 6'-cloro-2,3,5,6-tetra-hidro- [1,2']bipirazinil-4-carboxllicoPreparation of 6'-chloro-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl trifluoroacetate (a) 6'-Chloro-2,3,5- 6-tetrahydro- [1,2 '] bipyrazinyl-4-carboxylic acid

Aqueceu-se, à temperatura de refluxo, durante 1,5 horas, uma mistura de 10 mmole de 2,6-dicloropirazina e 21 mmole de N-BOC-piperazina, no seio de 15 ml de acetonitrilo. Concentrou-se a mistura reaccional e purificou-se por cromatografia (Si02; diclorometano/metanol a 95:5), para se obter o composto do titulo, sob a forma de um sólido incolor. EM (m/e): 299,2 (MH+, 100 %) (b) Trifluoroacetato de 6'-cloro-3,4,5,6-tetra-hidro-2H-[1,2']bipirazinilo 113A mixture of 10 mmole of 2,6-dichloropyrazine and 21 mmole of N-BOC-piperazine in 15 ml of acetonitrile was heated at reflux temperature for 1.5 hours. The reaction mixture was concentrated and purified by chromatography (SiO 2, dichloromethane / methanol 95: 5) to give the title compound as a colorless solid. MS (m / e): 299.2 (MH +, 100%) (b) 6'-Chloro-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl trifluoroacetate 113

Tratou-se uma solução de 2 mmole do éster terc-butílico do ácido 6'-cloro-2,3,5,6-tetra-hidro-[1,2']bipi-razinil-4-carboxílico, no seio de 10 mL de diclorometano, com 3 mmole de ácido trifluoroacético ' e agitou-se à temperatura ambiente, durante 17 horas. A concentração e a O- ^ cristalização no seio de éter de dietilo originou o composto do .título sob a forma de um sólido incolor. EM (m/e) : 198,0 (M+, 100 %)A solution of 6 mmol of 6'-chloro-2,3,5,6-tetrahydro- [1,2 '] bipi-razinyl-4-carboxylic acid tert-butyl ester in 10 ml dichloromethane was treated with 3 mmole of trifluoroacetic acid and stirred at room temperature for 17 hours. Concentration and crystallization in diethyl ether afforded the title compound as a colorless solid. MS (m / e): 198.0 (M +, 100%)

Exemplo 4.10Example 4.10

Preparação do cloridrato de amida do ácido 3,4,5,6-tetra-hidro-2H-[1,2']bipirazinil-5'-carboxílico (a) Éster terc-butílico do ácido 5'-carbamoil-2,3,5,6-te-tra-hidro-[1,2']bipirazinil-4-carboxílicoPreparation of 3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-5'-carboxylic acid amide hydrochloride (a) 5'-Carbamoyl-2,3- , 5,6-tetrahydro- [1,2 '] bipyrazinyl-4-carboxylic acid

Dissolveu-se 3 mmole do éster 5'-metílicQ do éster terc-butílico do ácido 2,3,5,6-tetra-hidro-[l,2']bipira-zínil-4,5'-dicarboxílico (exemplo 1.13 (a)), numa solução 7 molar de amónia gasosa, . no seio de metanol. O reactor foi fechado fortemente e aqueceu-se durante a noite, a noite 60° C. O arrefecimento das misturas da reacção levou à cristalização do composto do título. EM (m/e): 308,4 (MH+, 100 %) (b) Cloridrato da amida do ácido 3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinil-5'-carboxílico3-Methyl of 2,3,5,6-tetrahydro- [1,2 '] bipyrazin-4,5'-dicarboxylic acid tert-butyl ester 3 mmol (Example 1.13 ( (a)), in a 7 molar solution of ammonia gas,. in methanol. The reactor was tightly closed and heated overnight at 60 ° C. Cooling of the reaction mixtures led to the crystallization of the title compound. MS (m / e): 308.4 (MH +, 100%) (b) 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyrazinyl-5'- carboxylic acid

Agitou-se durante 1 hora, 0,25 mmole do éster terc- butílico do ácido 5'-carbamoil-2,3,5,6-tetra-hidro-[1,2']-bipirazinil-4-carboxílico, no seio de 1 mL de dioxano saturado com HC1 gasoso. A concentração da mistura reaccio- 114 nal originou o composto do título, sob a forma de um sólido incolor. EM (m/e): 208,3 (MH+, 100 %)0.25 mmol of 5'-carbamoyl-2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-carboxylic acid tert-butyl ester was stirred for 1 hour at of 1 mL of dioxane saturated with gaseous HCl. Concentration of the reaction mixture afforded the title compound as a colorless solid. MS (m / e): 208.3 (MH +, 100%)

Exemplo 4.11 íExample 4.11

Preparação de dimetil-(4-piperazin-l-il-[1,3,5]—triazin-2-il) -amina (a) Éster terc-butílico do ácido 4-(4-cloro-[1,3,5]-tria-zin-2-il)-piperazino-l-carboxílicoPreparation of dimethyl- (4-piperazin-1-yl- [1,3,5] triazin-2-yl) -amine (a) 4- (4-Chloro- [1,3, 5] -triaza-2-yl) -piperazine-1-carboxylic acid tert-butyl ester

Arrefeceu-se uma solução de 11 mmole de 2,4-diclo-rotriazina (patente de invenção WO 02/083654), no seio de 2 0 mL de acetonitrilo e tratou-se com 11 mmole de trietilamina e 11 mmole de' N-BOOpiperazina. Agitou-se a mistura reaccional durante 2 horas, a 0o C e depois durante 2 horas, à temperatura ambiente. A adição de 100 mL de salmoura e a extracção com acetato de etilo, originou o produto impuro que se purificou por meio trituração no seio de acetato de etilo. EM (m/e): 300,3 (MH+, 100 %) (b) Éster terc-butílico do ácido 4-(4-dimetilamino-[1,3,5]-tfiazin-2-il)-piperazino-1-carboxllicoA solution of 11 mmol of 2,4-dichlorotriazine (WO 02/083654) in 20 mL of acetonitrile was cooled and treated with 11 mmol of triethylamine and 11 mmol of N- Bpypiperazine. The reaction mixture was stirred for 2 hours at 0 ° C and then for 2 hours at ambient temperature. Addition of 100 mL of brine and extraction with ethyl acetate afforded the crude product which was purified by trituration in ethyl acetate. MS (m / e): 300.3 (MH +, 100%) (b) 4- (4-Dimethylamino- [1,3,5] -thiaziazin-2-yl) -piperazine-1 -carboxylic acid

Agitou-se à temperatura ambiente, durante 1 hora, uma solução de 2 mmole do éster terc-butílico do ácido 4-(4-cloro-[1,3,5]triazin-2-il)-piperazino-l-carboxílico, no seio de 15 mL de dimetilamina 2 M, no seio de metanol. A concentração e a purificação por cromatografia (Si02; acetato de etilo/ciclo-hexâno a 1:1), originou o composto do título, sob a forma de um sólido incolor. EM (m/e) : 309,1 (MH+, 100 %) (c) Dimetil-(4-piperazin-l-il-[1,3,5]triazin-2-il)-amina 115A solution of 4- (4-chloro-1,3,5-triazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester, 2 mmol, in 15 mL of 2M dimethylamine in methanol. Concentration and purification by chromatography (SiO2: 1: 1 ethyl acetate / cyclohexane) provided the title compound as a colorless solid. MS (m / e): 309.1 (MH +, 100%) (c) Dimethyl- (4-piperazin-1-yl- [1,3,5] triazin-2-yl) -amine

II

Arrefeceu-se uma solução de 1 mmole do éster terc-butílico do ácido 4-(4-dimetilamino-[1,3,5]triazin-2-il)-piperazino-l-carboxílico, no seio de 10 mL de diclorometano e tratou-se com 14 mmole de ácido trifluoroacético. Aqueceu-se a mistura reaccional até 40 °C, durante 30 minutos. Após o arrefecimento, adicionou-se 50 mL de hidróxido de sódio aquoso 2 M. Separou-se a camada orgânica, secou-se e concentrou-se, para se obter o composto do título, sob a forma de um óleo amarelado. EM (m/e) : 267,0 (M+CH3COO+, 100 %)A solution of 1 mmol of 4- (4-dimethylamino- [1,3,5] triazin-2-yl) piperazin-1-carboxylic acid tert-butyl ester was cooled in 10 mL of dichloromethane and was treated with 14 mmol of trifluoroacetic acid. The reaction mixture was warmed to 40 ° C for 30 minutes. After cooling, 50 mL of 2M aqueous sodium hydroxide was added. The organic layer was separated, dried and concentrated to give the title compound as a yellowish oil. MS (m / e): 267.0 (M + CH 3 COO +, 100%)

Exemplo 4.12Example 4.12

Preparação de 6'-metoxi-3,4,5,6-tetra-hidro-2H-[1,2']-bipi-razinilo (a) Éster terc-butílico do ácido 6'-metoxi-2, 3,5,6-tetra-hidro-[1,2']bipirazinil-4-carboxílicoPreparation of 6'-methoxy-3,4,5,6-tetrahydro-2H- [1,2 '] bipi-razinyl (a) 6'-Methoxy-2,3,5- , 6-tetrahydro- [1,2 '] bipyrazinyl-4-carboxylic acid

Dissolveu-se 1 mmole do éster terc-butílico de 6'-cloro-2,3, 5,6-tetra-hidro-[1,2']bipirazinil-4-carboxílico [exemplo 4.9 (a)], no seio de uma solução de metanolato de sódio (preparada por dissolução de 1 mmole de sódio no seio de 10 mL.de metanol). Aqueceu-se a mistura durante a noite, a 70 °C,, concentrou-se e purificou-se· o produto por cromatografia. (Si02; diclorometano/metanol a 99:1), para se obter o composto do título, sob a, forma de uma espuma incolor. EM (m/e): 295,3 (MH+, 100 %) (b) . 6'-Metoxi-3,4,5,6-tetra-hidro-2H-[1,2']bipirazinilo.1 mmol of 6'-chloro-2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-carboxylic acid tert-butyl ester [Example 4.9 (a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 10 mL of methanol). The mixture was heated overnight at 70 ° C, concentrated and the product purified by chromatography. (SiO 2, dichloromethane / methanol 99: 1) to give the title compound as a colorless foam. MS (m / e): 295.3 (MH +, 100%) (b). 6'-Methoxy-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl.

Preparou-se em analogia com o exemplo 4.10 (c) , a partir do éster terc-butílico do ácido 6'-metoxi-2,3,5,6- 116 tetra-hidro-[1,2']bipirazinil-4-carboxilico e ácido tri-fluoroacético. EM (m/e): 195,1 (MH+, 80 %)Prepared in analogy to example 4.10 (c) from 6'-methoxy-2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4- carboxylic acid and trifluoroacetic acid. MS (m / e): 195.1 (MH +, 80%)

Exemplo 4.13Example 4.13

Preparação de 2-metoxi-4-piperazin-l-il-[l,3,5]triazina (a) Éster terc-butílico do ácido 4-(4-metoxi-[1,3,5]tri-azin-2-il)-piperazino-l-carboxílicoPreparation of 2-methoxy-4-piperazin-1-yl- [1,3,5] triazine (a) 4- (4-Methoxy- [1,3,5] triazin-2 -yl) -piperazine-1-carboxylic acid

Dissolveu-se 1 mmole do éster terc-butílico do ácido 4-(4-cloro-[1,3,5]triazin-2-il)-piperazino-l-carboxílico [exemplo 4.11 a)], no seio de uma solução de metanolato de sódio (preparada por dissolução de 1 mmole de sódio no seio de 5 mL de metanol). Agitou-se a mistura à temperatura ambiente, durante 1 hora, concentrou-se e purificou-se o composto do título por recristalização no seio de acetato de etilo/ciclo-hexano. EM (m/e): 296,3 (MH+, 100 %) (b) 2-Metoxi-4-piperazin-l il-[1,3,5]triazina1 mmol of 4- (4-chloro- [1,3,5] triazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester [Example 4.11 (a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 5 mL of methanol). The mixture was stirred at room temperature for 1 hour, concentrated and the title compound was purified by recrystallization from ethyl acetate / cyclohexane. MS (m / e): 296.3 (MH +, 100%) (b) 2-Methoxy-4-piperazin-1-yl- [1,3,5] triazine

Preparou-se em analogia com o exemplo 4.10 (c) , a partir do éster terc-butílico do ácido 4- (4-metoxi-[1, 3,5]-triazin-2-il)-piperazino-l-carboxílico e ácido trifluoro-acético. EM (m/e): 196,4 (MH+, 100 %)Prepared in analogy to example 4.10 (c) from 4- (4-methoxy- [1,3,5] -triazin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m / e): 196.4 (MH +, 100%)

Exemplo 4.14Example 4.14

Preparação do ácido 2-dimetilcarbamoiloxi-5-metano-sulfo-nil-benzóico (a) Éster benzílico do ácido 2-hidroxi-5-metano-sulfonil-benzóico 117Preparation of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid (a) 2-Hydroxy-5-methanesulfonyl-benzoic acid benzyl ester

Adicionou-se, lentamente, 5 mmole de cloridrato de N-(3-dimetilaminopropil)-Ν'-etil-carbodi-imida a uma suspensão agitada de 5 mmole do ácido 2-hidroxi-5-metano-sulfonil-benzóico, 5 mmole de álcool benzilico e 0,5 mmole de 4-dimetilaminopiridina, no seio de 10 mL de aceto-nitrilo. Agitou-se a mistura durante a noite, à temperatura ambiente, concentrou-se e tratou-se com 10 mL de água. Adicionaram-se algumas gotas de ácido clorídrico diluído para acidificar a solução. Filtrou-se o sólido resultante e purificou-se por cromatografia (S1O2; acetato de etilo/ciclo-hexano a .3:7), para se obter o composto do título, sob a forma' de um sólido incolor. EM (m/e) : 305,0 (M-II, 100 %) (b) Éster benzilico do ácido 2-dimetilcarbamoiloxi-5-metano-sulfonil-benzóico5 mmol of N- (3-dimethylaminopropyl) -β-ethylcarbodiimide hydrochloride was added slowly to a stirred suspension of 5 mmol of 2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and 0.5 mmol of 4-dimethylaminopyridine in 10 mL of acetonitrile. The mixture was stirred overnight at room temperature, concentrated and treated with 10 mL of water. A few drops of dilute hydrochloric acid were added to acidify the solution. The resulting solid was filtered and purified by chromatography (SiO 2, ethyl acetate / cyclohexane 3: 7) to give the title compound as a colorless solid. MS (m / e): 305.0 (M-II, 100%) (b) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester

Tratou-se uma mistura de 1 mmole do éster benzilico do ácido 2-hidroxi-5-metano-sulfonil-benzóico, 1,5 mmole de N-metilmorfolina e 0,2 mmole de 4-dimetilaminopiridina, no seio de 4. mL de dimetilformamida, com 1,3 mmole de cloreto de N,N-dimetilcarbamoilo* Agitou-se a mistura reaccional a 60 ÍC, durante 48 horas,' concentrou-se in vacuo e recolheu-se o resíduo em 5 mL de água. A acidificação com ácido clorídrico diluído e a extracção com acetato de etilo originou um produto impuro que se purificou por croma-tografia (SÍO2; acetato de etilo/ciclo-hexano a 1:1) . EM (m/e) : 378,3. (MH+, 100 %) (c) Ácido 2-dimetilcarbamoiloxi-5-metano-sulfonil-benzóicoA mixture of 1 mmol of 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 mL of dimethylformamide was treated with 1.3 mmol of N, N-dimethylcarbamoyl chloride. The reaction mixture was stirred at 60 ° C for 48 hours, concentrated in vacuo and the residue taken up in 5 mL of water. Acidification with dilute hydrochloric acid and extraction with ethyl acetate gave a crude product which was purified by chromatography (SiO 2, ethyl acetate / cyclohexane 1: 1). MS (m / e): 378.3. (MH +, 100%) (c) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid

Dissolveu-se 1 mmole do éster benzilico do ácido 2-dimetilcarbamoiloxi-5-metano-sulfonil-benzóico, no seio de 5 mL de metanol. Adicionou-se 25 mg de paládio a 10 % em 118 carvão e hidrogenou-se a mistura reaccional, à temperatura ambiente, para se obter o composto do titulo, sob a forma de um sólido ligeiramente amarelado. EM (m/e): 288,0 (MH+, 66 %)1 mmol of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester was dissolved in 5 mL of methanol. 25 mg of 10% palladium on charcoal was added and the reaction mixture was hydrogenated at room temperature to give the title compound as a slightly yellow solid. MS (m / e): 288.0 (MH +, 66%)

Em analogia com o exemplo 5, prepararam-se os compostos 327 a 355 do quadro que se segue, a partir do derivados ácidos e derivados de piperazina:In analogy to example 5, compounds 327 to 355 of the following table were prepared from the acid derivatives and piperazine derivatives:

Exemp. Ν'. Nome Sistemático Materiais Iniciais EM encont. (MH+) 327 (6-etoxi-2-fluoro-3-metano-sulfonil-fenil)-[4-(4-métano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 6-etoxi-2-fluoro-3-metano-sulfonil-benzóico (composto 4.1) 485,4 . 328 (2-isopropoxi-5-metano-sul-fonil-fenil)-[4-(4-trifluo-rometanò-sulfonil-fenil)-piperazin-l-il]-metanona 1- (4-trifluorometano-sulfonil-fenil)-piperazina (composto 4.2) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 552,0 (M+NH/.) . 32 9, (2-ciclopentiloxi-5-raetano-sulfonil-fenil)-[4-(4-trifluorometano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometano-sulfonil-fenil)-piperazina (composto 4.2) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 578,0 (M+NH4+) 330 (2-isobutoxi-5-metano-sulfonil-fenil)-[4-{4-trifluorometano-sulfonil-fenil)- piperazin-l-il]- 1-(4-trifluorometano-sulfonil-fenil)-piperazina (composto 4.2) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 566,1 (M+NH/) 331 [4-(2,4-Bis-trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona cloridrato de l-(2,4-bis-trifluorometil-fenil)-piperazina (composto 4.3) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 539,2 332 [4-(2,4-bis-trifluorómetil-fenil)-piperazin-l-il]-(2-ciclopentiloxi-5-metano-sulfonil-fenil)-metanona cloridrato de l-(2,4-bis-trifluorometil-fenil)-piperazina (composto 4.3) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 565,3 333 [4-(2,4-bis-trifluorometil-fenil)-piperâzin-l-il]-(2-isobutoxi-5-metano-sulfonil- cloridrato de l-(2,4-bis-trifluorometil-fenil)-piperazina (composto 4.3) e ácido 2- 553,2 119 fenil)-metanona isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 334 (2-isobutoxi-5-metano-sulfonil-fenil)—{4—[4—(5— metil-[1,2,4]-oxadiazol-3-il)-fenil]-piperazin-l-il}-metanona cloridrato de 1-[4-(5-metil-[1,2,4]oxadiazol-3-il)-fenil]-piperazina (composto 4.4) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 499,1 335 (2-ciclopentiloxi-5-metano-sulfonil-fenil)—{4—[4—(5— metil-[1,2,4]-oxadiazol-3-il)-fenil]-piperazin-l-il}-metanona cloridrato de l-[4-(5-metil-[1,2,4]-oxadiazol-3-il)-fenil]-piperazina (composto 4.4) e ácido 2-ciclopentiloxi-5-métano-sulfonil-benzóico (composto 1.6) 511,4 336 (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-oxazol-2-il-fenil)-piperazin—1-il]-metanona 1- (4-oxazol-2-il-fenil)-piperazina (composto 4.5) e ácido 2- isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 484,4 337 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(4-oxazol-2-il-fenil)-piperazin-l-il]-metanona cloridrato de 1-(4-oxazol-2-il-fenil)-piperazina (composto 4.5) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 496,4 338 (2-isopropoxi-5-metano-sulfonil-fenil)-{4-[4-(5-metil-[1,3,4]-oxadiazol-2-' il)-fenil]-piperazin-l-il}-metanona cloridrato de 1-[4-(5-metil-[1,3,4]-oxadiazol-2-il)-fenil]-piperazina (composto 4.6) e ácido 2-i s opropoxi-5-met ano-sulfoni1-benzóico (composto 1.2) 465,3 339 (2-isobutoxi-5-metano-sulfonil-fenil)—{4—[4 —(5-metil-[1,3,4]-oxadiazol-2-il) -fenil'] -piperazin-l-il}-metanona cloridrato de 1-[4-(5-metil-. [1,3,4]-oxadiazol-2-il)-fenil]-piperazina (composto 4.6) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 499,2 340 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-{4-[4-(.5-metil-[1,3,4]-oxadiazol-2-ií)-fenil]-piperazin-l-il}-metanona cloridrato de l-[4-(5-metil-[1,3., 4] -oxadiazol-2-il) -fenil] -piperazina (composto 4.6) e ácido 2-clclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 511,3 341 . (2-isobutoxi-5-metano-sulfonil-fenil)-(4-[4-(2-metil-2H-tetrazol-5-il)-fenil]-piperazin-l-il}-metanona cloridrato de 1-[4-(2-metil-2H-tetrazol-5-il)-fenil]-piperazina (composto 4.7) e ácido etano-sulfonil-benzóico do ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 499, 1 342 éster metilico do áçido metilcarboxilico do ácido 4-(2-isopropoxi-5-4-(2- éster metilico do ácido 3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinil-5'-carboxílico; 463,4 120 isopropoxi-5-metano-sulfonil-benzoil)-3,4,5,6-tetra-hidro-2H-[1,2']-bipirazínil-5'-carboxilico cloridrato (composto 4.8) e 2-(composto 4.8) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 343 éster metálico do ácido 4-(2-isobutoxi-5-metano-' sulfonil-metano-sulfonil-benzoil)-3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinll-5'-carboxilico éster metálico do ácido 3,4,5,6-tetra-hidro-2H-[1,2' ] — bipirazinil-5'-carboxilico; cloridrato (composto 4.8) e ácido 2-isobutoxi-5-metano-sul£onil-benzóico (composto 1.3) 477,1 344 (6'-cloro-2,3,5,6-tetra-hidro-[1,2' ]-bipirazinil-4-il) - (2-isopropoxi-5-metano-sulfonil-fenil)-metanona ácido 6'-cloro-3,4,5,6-tetra-hidro-2H-[1,2'] - bipirazinil- ' trifluoro-acético (composto 4.9) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1..2) 439,1 345 amida do ácido 4-(2-isopropoxi-5-metan.o-sulfoníl-benzoil)-3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinil-5'-carboxilico amida do ácido 3,4,5,6-tetra-hidro-2H- [1,2']-bipirazinil-5'-carboxilico; cloridrato (composto 4.10} e áçido 2-isopropòxi-5-metano-sulfonil-benzóico (composto 1.2) 448,3 346 amida do ácido 4-(2-isobutoxi-5-metano-salfonil-benzoil)-3,4,5,6-tetra-hidrõ-2H-[1,2']-bipirazinil-5'-carboxilico amida do ácido 3,4,5,6-tetra-hidro-2H- [1,2']-bipirazinil-5' -carboxilico; cloridrato (composto 4.10) e ácido 2-isobutoxi-5- metano-sulfonil-benzóico (composto· 1.3) 462,3 347 [4-(4-dimetilamino-[1,3,5]— trlazln-2-il)-piperazin-1-il]-(2-isobutoxi-5- metano-sul fonil-fenil) -metanona dimetil-(4-piperazin-l-il-[1,3,5]-triazin-2-il}-amina (composto 4.11) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 463,3 348 [4-(4-dimetilamino-[1,3,5]-triazin-2-il)-piperazin-1-il]-(2-isopropoxi-5-metano-sulfonilfenil)-metanona dimetil-(4-piperazin-l-il-[1,3,5]-triazin-2-il)-amina (composto 4.11) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 449,3 349 (2-isopropoxi-5-metano-sulfonil-fenil)-(6' -metoxi-2,3,5,6-tetra-hidro-[1,2']-biplrazinil-4-il)-metanona ácido' 6'-metoxi 3,4,5,6-tetra-hidro-2H-[12']-bipirazinil-trifluoro-acético (composto 4.12) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 435,2 350 (2-isopropoxi-5-metano- 2-metoxl-4-p.iperazin-l-il- 436,4 121 sulfonil-f.enil)-[4-(4-metoxi-[1,,3,5]-triazin-2-il)-piperazin-l-il]-metanona [1,3,5]-triazina (composto 4.13) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 351 éster 4-metano-sulfonil-2-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]- fenílico do ácido dimetil- '·. carbâmico. 1- (4-trifluoroiiietil-fenil)-piperázina (comercial) e ácido 2-dimeti1carbamoi1oxi-5-metano-siilfonil-benzóico (composto 4.14) .500,4 352 éster 2-[4-(2-flucre-4-metano-sulfonil-fenil)-piperazino-l-carbonil]-4-metano-sulfonil-fenílico do ácido dimetil-carbâraico 1- (2-flnoro-4-metano-sulfonil-fenii)-piperazina. (comercial) e. ácido 2-dimetilcarbamoiloxi-5-metano-sulfonii-berizóico (composto 4.14) 528,3 ' 353 (2-ciclopropilmetoxi-5-metano-suifonil-fenil)-(4- . fenil-piperazin-l-il)-metanona. 1-féni'1-piperazina (comercial) e ' ácido 2-ciclopropilmétoxi-5-metano-sul.fonil-bénzóico (composto 1.4) . 415,5 354 (2-ciclopròpilmetoxi-5- ' r.etanc—sulfcnil-fer.il) - [4t -.(4-metoxi-fenil)-piperazin-l-il] -metanona- 1-(4imetoxi-fenil)-piperazina (comercial) é ácido 2-ciclopropilmetoxi-5-metano-su.lfonil-benzóico (composto 1.4) 445,3 355.· (2-ciclopropilmetoxi-5-iaetano-sulfònilfenil) -.[4- ('4-hidroxi-fenilj-piperazin-l-il] -metanona . 4-piperazin-l-il-fenol (comercial) e ácido 2-cicÍopropilmetoxi-5-métano-sulfonil-benzóico (composto 1.4) - 431,4Exemp. Ν '. Systematic Name Initial Materials EM Found. (MH +) 327 (6-ethoxy-2-fluoro-3-methanesulfonyl-phenyl) - [4- (4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (4-methano- sulfonyl-phenyl) -piperazine (commercial) and 6-ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid (compound 4.1) 485.4. 328 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethanesulfonyl-phenyl ) -piperazine (compound 4.2) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 552.0 (M + NH 4). (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethanesulfonyl-phenyl) -pyrrolidine-2-carboxylic acid (2-cyclopentyloxy-5-methanesulfonyl- piperazine (compound 4.2) and 2-cyclopentyloxy-5-methanesulfonylbenzoic acid (compound 1.6) 578.0 (M + NH4 +) 330 (2-isobutoxy-5-methanesulfonyl-phenyl) - [4- [4- 1-yl] -1- (4-trifluoromethanesulfonyl-phenyl) -piperazine (compound 4.2) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) , 1 (M + NH) 331 [4- (2,4-Bis-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone hydrochloride 1- (Compound 4) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 539.2 332 [4- (2,4-bis-trifluoromethyl- phenyl) -piperazin-1-yl] - (2-cyclopentyloxy-5-methanesulfonyl-phenyl) -methanone 1- (2,4-bis-trifluoromethyl-phenyl) -piperazine hydrochloride (compound 4.3) and 2- cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 565 , 3- (2,4-bis-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl- ) -piperazine (compound 4.3) and 2-isobutoxy-5-methanesulfonyl-phenyl) - (4-methoxyphenyl) -methanone isobutoxy-5-methanesulfonyl- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -piperazin-1-yl} -methanone hydrochloride 1- [4- (5-methyl- [1,2- , 4-oxadiazol-3-yl) -phenyl] -piperazine (compound 4.4) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) 499.1335 (2-cyclopentyloxy-5-methanesulfonyl- phenyl) - {4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -piperazin-1-yl} -methanone hydrochloride 1- [4- (5- methyl-1,2,4] oxadiazol-3-yl) -phenyl] -piperazine (compound 4.4) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 511.4 336 (2-isobutoxy -5-methanesulfonyl-phenyl) - [4- (4-oxazol-2-yl-phenyl) -piperazin-1-yl] -methanone 1- (4-oxazol-2-yl-phenyl) -piperazine 4.5) and 2-isobutoxy-5-methanesulfonic acid (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (4-oxazol-2-yl-phenyl) -piperazin-1-yl] -methanone hydrochloride 1- (4-oxazol-2-yl-phenyl) -piperazine (compound 4.5) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 496.4 338 (2-isopropoxy-5-methanesulfonyl -phenyl) - {4- [4- (5-methyl- [1,3,4] oxadiazol-2'yl) -phenyl] -piperazin-1-yl} -methanone hydrochloride 1- [4- 5-methyl-1,3,4] oxadiazol-2-yl) -phenyl] -piperazine (compound 4.6) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 465.3 339 (2-isobutoxy-5-methanesulfonyl-phenyl) - {4- [4- (5-methyl- [1,3,4] -oxadiazol-2-yl) -phenyl] -piperazin-1-yl} 1- [4- (5-methyl- [1,3,4] oxadiazol-2-yl) -phenyl] -piperazine (compound 4.6) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) 499.2 340 (2-cyclopentyloxy-5- (4-methyl-1,3,4-oxadiazol-2-yl) -phenyl] -piperazin-1-yl} -methanone hydrochloride salt of 1- [4- (5-methyl- [1,3,4-oxadiazol-2-yl) -phenyl] -piperazine (compound 4.6) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 511 , 3441. (2-isobutoxy-5-methanesulfonyl-phenyl) - (4- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -piperazin-1-yl} -methanone hydrochloride 1- [ 2-isobutoxy-5-methanesulfonyl-benzoic acid ethanesulfonyl-benzoic acid (compound 1.3) 499, found: 4- (2-methyl-2H-tetrazol-5-yl) -phenyl] Methyl ester of 4- (2-isopropoxy-5-4- (2-methyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl- 5-methanesulfonyl-benzoyl) -3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-5'-carboxylic acid hydrochloride (compound 4.8) and 2- (compound 4.8) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 343 4- (2-isobutoxy-5-methanesulfonyl-methanesulfonyl-benzoyl) ) -3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-5'-carboxylic acid 3,4,5,6-tetrahydro-2H- [ 2 '] -bipyrazinyl-5'-carboxylic acid, hydrochloride (compound 4.8) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1 (3'-chloro-2,3,5,6-tetrahydro- [1,2 '] -bipyrazinyl-4-yl) - (2-isopropoxy-5-methanesulfonyl- phenyl) -methanone 6'-chloro-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-trifluoroacetic acid (compound 4.9) and 2-isopropoxy-5-methane acid (2-isopropoxy-5-methanesulfonyl-benzoyl) -3,4,5,6-tetrahydro-2H-pyrazol- [1,2 '] - bipyrazinyl-5'-carboxylic acid amide 3,4,5,6-tetrahydro-2H- [1,2'] bipyrazinyl-5'-carboxylic acid amide; hydrochloride (compound 4.10) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 448.3 346 4- (2-isobutoxy-5-methanesulfonylbenzoyl) -3,4,5- , 3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl-5', 6-tetrahydro-2H- [1,2 '] bipyrazinyl-5'-carboxylic acid amide, 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) 462.3 347 [4- (4-dimethylamino- [1,3,5] -triazol-2-yl) yl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone dimethyl- (4-piperazin-1-yl- [1,3,5] -triazin-2-yl (4-dimethylamino- [1,3,5] triazin-2-yl) amine (compound 4.11) and 2-isobutoxy-5-methanesulfonyl-benzoic acid 1-yl] - (2-isopropoxy-5-methanesulfonylphenyl) -methanone dimethyl- (4-piperazin-1-yl- [1,3,5] -triazin-2-yl) -amine (compound 4.11) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 449.3 349 (2-isopropoxy-5-methanesulfonyl-phenyl) - (6'-methoxy-2,3,5,6 -tetrahydro- [1,2 '] - biplrazinyl-4- yl) -methanone 6'-methoxy-3,4,5,6-tetrahydro-2H- [12 '] - bipyrazinyl-trifluoroacetic acid (compound 4.12) and 2-isopropoxy-5-methanesulfonyl- benzoic acid (compound 1.2) 435.2 350 (2-isopropoxy-5-methano-2-methoxy-4-piperazin-1-yl) -acetyl] - [4- (4-methoxy- - [1,3,5] -triazin-2-yl) -piperazin-1-yl] -methanone [1,3,5] -triazine (compound 4.13) and 2-isopropoxy-5-methanesulfonyl- benzoic acid (compound 1.2) 351 dimethyl-4-methanesulfonyl-2- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -phenyl ester. carbamic acid. 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-dimethylcarbamoyl-5-methanesulfonyl-benzoic acid (compound 4.14) .500.4 352 2- [4- (2-fluoro-4-methane 4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-methanesulfonyl-phenyl ester 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine. (commercial) e. 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid (compound 4.14) 528.3353 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - (4-phenyl-piperazin-1-yl) -methanone. 1-phenyl-piperazine (commercial) and 2-cyclopropylmethy-5-methanesulfonyl-benzoic acid (compound 1.4). 415.5 (4-methoxy-phenyl) -piperazin-1-yl] -methanone-1- (4-methoxy-phenyl) -piperazin- ) -piperazine (commercial) is 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 445.3 355. (2-cyclopropylmethoxy-5-methanesulfonylphenyl) - [4- (4- 4-piperazin-1-yl-phenol (commercial) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) - 431.4

Exemplo 356Example 356

Preparação de óxima de 1-{3-fluoro-4-[4-&lt;2-isopropoxi-5-metano-sulfonil-benzoil) r-piperazin-l-il] -fenil}-etanonaPreparation of 1- {3-fluoro-4- [4- [2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone oxime

Dissolveu-se 0,12 mmole de . 1-{3-fluoro-4-[4-(2-isopro-poxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-fenil}-etário na, no seio de 1 ir.L de uma mistura 1:1 de etanol e água. Adicionou-se 0,8 mmole de cloridrato de hidroxilamina, seguido de 8,4' mmole de acetato de ' sódio,. Agitou-se a mistura; resultante'durante a noite, à temperaturaambiente, diluiu-se coir. água, filtrou-se, lavou-se e secou-se, para se obter o composto do titulo sob a forma de Um sólido incolor. SM (m/e) : 478,2 (MH+, . 100 %) 1220.12 mmol of. 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethane in 1 ml of a 1: 1 mixture of ethanol and water. Hydroxylamine hydrochloride (0.8 mmol) was added followed by 8.4 mmol sodium acetate. The mixture was stirred; at room temperature, diluted with water. water, filtered, washed and dried, to provide the title compound as a colorless solid. MS (m / e): 478.2 (MH +, 100%).

Exemplo 357Example 357

Preparação de O-metil-óxima de l-{3-fluoro-4-[4-(2-isopro-poxi-5-metano-sulfon.il-benzoil) -piperazin-l-il] -fenil}-eta-nonaPreparation of 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethane- ninth

Dissolveu-se 0,12 mmole de 1-{3-fl.uoro-4- [4- (2-iscprc— poxi-5-metano-sulfoni.l-be.nzoil) -piperazin-l-il] -fenil}-eta-nona,' no seio. de 1 mL de uma mistura 1:1· de etanol e agua. Adicionou-se 0/8 mmole de cloridrato de O-métil-hidroxil-amina, seguido: de 8,4 mmole de acetato'de sódio. Agitou-se a: pasta durante a noite, à temperatura ambiente, diluiu-se com água, extraiu-se com acetato de etilo, secou-se e concentrou-se. Triturou-se a goma resultante com éter- de dietilo/heptano, para- se obter o composto do titulo sob. a formá de um sólido incolor. EM (m/e): 492,3 (MH+, 100 %)0.13 mmol of 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl } -one-nona, in the breast. of 1 mL of a 1: 1 mixture of ethanol and water. O-methylhydroxylamine hydrochloride (0.8 mmol) was added followed by 8.4 mmol sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was triturated with diethyl ether / heptane to give the title compound as a white solid. to form a colorless solid. MS (m / e): 492.3 (MH +, 100%)

Exemplo 4.15Example 4.15

Preparação de {2,6-difluoro-3-metaho-sulfonil-fenil)-[4-(2-fluoro-4-metano-snlfonil-fenil)-piperázin-l-il)-metanòna (a) Acido 3-clorosulfonil-2,6-difluoro-benzóicoPreparation of 3-chlorosulfonyl (3-methoxyphenyl) -piperazin-1-yl) -methanone (a) Preparation of (2,6-Difluoro-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl- -2,6-difluoro-benzoic acid

Dissolveu-se 77' mmole de ácido . 2, 6-d.if luorobenzóico, no seio de 15,5 mL. de 'ácido cloro-sylfónico e agitou^se durante 2 horas, a 150 °C. Arrefeceu-se a. mistura reaccio-nal para a temperatura ambiente e verteu-se em 100 mL de gelo/água. Filtrou-se o sólido e secou-se, para se obter o composto do titulo sob a forma de um. sólido incolor. EM (m/e): 255,1 (M-H, 44 %) .(.b) ' Ácido 2,6-difluoró-3-sulfino-benzóico77 mol of acid was dissolved. 2,6-difluorobenzoic acid in 15.5 mL. of chlorosulfonic acid and stirred for 2 hours at 150 ° C. A. The reaction mixture was cooled to room temperature and poured into ice / water (100 mL). The solid was filtered and dried, yielding the title compound as a white solid. colorless solid. MS (m / e): 255.1 (M-H, 44%). 2,6-Difluoro-3-sulfino benzoic acid

Dissolveu-se 240 mmole de sulfito de sódio, no. seio de 150 mL . de água. Adicionou-se 32 mmole de' ácido, 3-clorosulfonil-2, 6-dif luoro-benzóico,. com .agitação', durante um período de cerca' de 20 minutos. Após. a agitação durante mâis 1 hora, à temperatura ambiente, arrefeceu-se a mistura e acidificou-se com ácido sulfúricò aquoso a.20 %.. Extraiu-se o produto com acetato de etilo, para se. obter; o composto, do título sob a formade umsólido incolor. EM (m/e): 221,3 (M-H, 34 %.) (c) Ácido. 2,6-dif luoro-3-metano-sulfonil-benzóico240 mmol of sodium sulfite, no. 150 ml. of water. 32 mmol of 3-chlorosulfonyl-2,6-difluoro-benzoic acid was added. with stirring, for a period of about 20 minutes. After. the mixture was cooled and acidified with 20% aqueous sulfuric acid. The product was extracted with ethyl acetate to give the title compound as a white solid. get; the title compound as a colorless solid. MS (m / e): 221.3 (M-H, 34%.) (C) Acid. 2,6-difluoro-3-methanesulfonyl-benzoic acid

Agitou-se à temperatura ambiente, durante 30. minutos, uma. suspensão de 18 mmole de carbonato de sódio e 9 mmole. de ácido 2,6-dif luoro-3-sulfinc-benzóico,- no. seio de 30 mL de metanol è depois aqueceu-se a 60 °C. Adicionou-se 24 mmole de iodeto . de. &quot;me ti lo. e aqueceu-se a mistura reaccion.al. durante a noite, a 60 °C. Diluiu-se. a mistura reaccional com água e extraiu-se com acetato de etilo.. Deitou-se fora a fase orgânica e acidificou-se a' fase aquosa por meio da adição de ácido clorídrico concentrado. A extracção com acetato de etilo, originou o composto do título/; sob a forma- de , um sólido ligeiramente acastanhado. EM - (m/e) :·. 235,1 (M-H, 16 %) (d)· .. (2,6-Difluoro-3-metano-sulfonií-fenil) - [4 - (2-fluoro-4-. metano-sulfonil-fenll) -piperazin-l-il] -riietanonaThe mixture was stirred at room temperature for 30 minutes. suspension of 18 mmol of sodium carbonate and 9 mmol. of 2,6-difluoro-3-sulfin-benzoic acid, no. of 30 ml of methanol and then heated to 60 ° C. 24 mmol of iodide was added. in. &quot; and the reaction mixture was heated. overnight at 60 ° C. Diluted. the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase acidified by the addition of concentrated hydrochloric acid. Extraction with ethyl acetate afforded the title compound; in the form of a slightly tan solid. In me) :·. 235.1 (MH, 16%) (d) · (2,6-Difluoro-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine -1-yl] -ethietanone

Preparou-se este composto em analogia com c exemplo 5, a partir . de. 1- (2-fluoro-4-metano-sulfonil-fenil)·-piperazina e do ácido. . 2,6-difluoro-3-metano-sulfonil-benzóico. EM (m/e): 477,0 (MH1, 67 %)This compound was prepared in analogy to example 5, in. 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine and of the acid. . 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m / e): 477.0 (MH +, 67%)

Exemplo 4.16 124.Example 4.16 124.

Preparação de 4-{4-(2,e-difluoro-S-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitriloPreparation of 4- {4- (2'-difluoro-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile

Preparou-se em analogia com o exemplo 5, a partir de 4-pÍpe.razin-l-ii-benzonitrilo e&quot; do. ácido 2, 6-difluoro-3-metano-siilfonil-benzóico. EM (m/e): 406, 3. (ME*, 84 %)Prepared in analogy to example 5 from 4-pentyrazin-1-yl-benzonitrile and &quot; of. 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m / e): 406.3 (M +, 84%).

Exemplo 358Example 358

Preparaçãp de &lt;2-ciclopentilo5s:i-6-etoxi-3-metano-sul£onil-fenil)-[4-(4-metano-sulfonil-fenil)-piperazin-l-il]-metano-na2-Cyclopentyl-6-ethoxy-3-methanesulfonyl-phenyl) - [4- (4-methanesulfonyl-phenyl) -piperazin-1-yl] -methane-na

Adicionou-se 0,12 mmole de. (e-etOxi^-fluoro-S-metano-sulfonil-fenil)- [4- (4-metano-sulfonil-fenil) -piperazin-d-il]-metanona (exemplo 55) a uma solução de ciclopentariolato de. sódio (preparado .a partir de 1 mmole de sódio dissolvido no ; seio de 1 rr.L de ciçlopentanoi) . Aqueceu-se a mistura durante 1 tora, a 80 °C, verteu-se em gelo/água e extraiu-se com acetato de etilo. A cromatografia (S1O2; acetato de etilo), originou o composto do- titulo sob a forma de um sólido ligeiramente amarelado. EM (rr./é) : 551,1 (MH+, 29 %)0.12 mmol of. (e-ethoxy) -fluoro-S-methanesulfonyl-phenyl) - [4- (4-methanesulfonyl-phenyl) -piperazin-d-yl] -methanone (example 55) was added to a solution of cyclopentylate. (prepared from 1 mmole of sodium dissolved in 1 ml of cyclopentane). The mixture was heated for 1 hour at 80 ° C, poured into ice / water and extracted with ethyl acetate. Chromatography (SiO2, ethyl acetate) afforded the title compound as a slightly yellow solid. MS (rt / e): 551.1 (MH +, 29%)

Exemplo 359Example 359

Preparação de (2,6-di-isopropoxi-3-metano—sulfonil-fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-meta-nonaPreparation of (2,6-diisopropoxy-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone

Adicionou-se 0,27 mmole de 2,6-difluoro-3-metano-sul-fonil-fenil)-[4- (2-fluoro-4-metano-sulfonil-fenil).-piperazin-l-il] -metanóna (exemple 4.15) a uma solução de iso-propanolato de sódio (preparada dissolvendo 3 mmole de sódio ·, em 2' nL de isoprepanol) . ' Aqueceu-se a mistura 125 reaccional sob refluxo, durante- 5 horas, arrefeceu-se, dil.uiu-se com água e extraiu-se com acetato de etilo, para se obter o composto do titulo sob a forma de um sólido ligeiramente amarelado. EM (m/e): 557,3 (MH+, 66 %)0.27 mmol of 2,6-difluoro-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - methanone (Example 4.15) was added to a solution of sodium iso-propanolate (prepared by dissolving 3 mmole of sodium in 2 nl of isopropanol). The reaction mixture was heated under reflux for 5 hours, cooled, diluted with water and extracted with ethyl acetate to give the title compound as a slightly off-white solid. yellowish. MS (m / e): 557.3 (MH +, 66%)

Exemplo 360Example 360

Preparação de (2-fluoro-6-isopropoxi-3-metano-sulfonil-fe-nil) - [4- (2-fluorô“4-metano-s,ulfon.il-fenil) -piperazin-l-il] -metanonaPreparation of (2-Fluoro-6-isopropoxy-3-methanesulfonyl-phenyl) - [4- (2-fluorophenylsulfonyl) phenyl] piperazin-1-yl] - methanone

Dissolveu-se. 0,2 mmole de (2,6-difluoro-3-metano-sul-fonil-fenil) -[4-{2-fluoro-4-metano-sulfonil-fenil) -piperá-zin-l-il]-metanona .numa solução de isopropanolato de sódio (preparada por· dissolução de 0,2. mmole de sódio no seio de 1 mi de isopropanol).Aqueceu-se a mistura reaccional até 50 °C, - durante 2 horas, depois agitou-se à temperatura ambiente, durante 48 horas. Diluiu-se a solução com água. e extraiu-se com acetato de etilo. Purificou-se'o produto por cromatografia (Si02; acetato de etilo/ciclo-hexanò a' 9:1)&quot;, para- se obter o composto do titulo sob a forma de um sólido incolor. EM (m/e): 517,1 (MH*, 100 %)Dissolved. 0.2 mmol) of (2,6-difluoro-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone in a solution of sodium isopropanolate (prepared by dissolving 0.2 mmole of sodium in 1 ml of isopropanol). The reaction mixture was heated to 50 ° C for 2 hours, then stirred at at room temperature for 48 hours. The solution was diluted with water. and extracted with ethyl acetate. The product was purified by chromatography (SiO2, ethyl acetate / cyclohexane 9: 1) to give the title compound as a colorless solid. MS (m / e): 517.1 (MH +, 100%)

Exemplo'361 .Example 361.

Preparação de (6-ciclopentiloxi-2-fluoro-3-metano-sulfonil-fenil)-[4-{2-fluoro-4-metano“Sulfonil-fenxl)-piperazin-l-il] -metanonaPreparation of (6-cyclopentyloxy-2-fluoro-3-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone

Preparou-se o &quot;composto em analogia com o exemplo 358, a partir de (2, 5-difluoro-3-:tieranc—sulfcnil-fenil) - [4- (2-fluoro-4-metano-sulfonil-fenil) -pipèra.zin-l-il] -metanona' ' e· ciclopentanolato de sódio. EM (m/e): 560,5 . (M+NH4+, .43.%;) 126The compound was prepared in analogy to example 358 from (2,5-difluoro-3- (phenylsulfanyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-yl] -methanone and sodium cyclopentanolate. MS (m / e): 560.5. (M + NH 4 +, .43%)

Exemplo 362Example 362

Preparação de 4-[4-(2-fluoro-6-isopropoxi-3-metano-sulfo-nil-benzoil)-piperazin-l-il]-benzonitriloPreparation of 4- [4- (2-fluoro-6-isopropoxy-3-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile

Preparou-se c composto em analogia cora o exemplo 359, a partir de 4-[4-(2,6-difluoro-3-metano-sulfónil-benzoil)-piperazin-l-il]-benzonitrilo e isopropanolato. de. sódio.. EM (ra/e) : 4.46,0 (MH+, 49 %)The compound was prepared in analogy to example 359 from 4- [4- (2,6-difluoro-3-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile and isopropanolate. in. sodium .. MS (Rf / e): 4.46.0 (MH +, 49%)

Exemplo 5.1Example 5.1

Preparação dè 1-(3-fluoro-4-trifluorometil-fenil)-piperazi-na (a) Éster terc-butílico· do ácido 4-(3-fluoro-4-trifluoro-. ' metil-fenil).-piperázino^l-carbOxllicoPreparation of 1- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine (a) 4- (3-Fluoro-4-trifluoromethylphenyl) 1-carboxylic acid

Aqueceu-se durante 16 horas, a .80 °C,. uma mistura de 4,9 rrnnole de 4-cloro-2-fluorobenzòtrifluoretò, .5,9 mmole de n-Eoc-piperazina, 0,05 mmole- de acetato de paládio, 6,9 mmole de t-butóxido. de sódio e 0,49 mmole de 2- (di-t-butilfosfino)bifenilo, no seio de 10 ml de tolueno. Depois de se arrefecer para TA, diluiu-se a mistura com éter, .filtroU-se a suspensão em. decalite e evaporou-se o filtrado. Purificou-se o resíduo em sílica, eluindo-se com um gradiente de heptano/EtOAc, .para. se obter, após evaporação, o composto do.título. (b) 1- (3.-Fluoro-4-trifluorometíl-fenil) -piperazina ..It was heated for 16 hours at .80 ° C. a mixture of 4.9 mmol of 4-chloro-2-fluorobenzotrifluoride, 5.5 mmole of n-Eoc-piperazine, 0.05 mmole of palladium acetate, 6.9 mmol of t-butoxide. of sodium and 0.49 mmol of 2- (di-t-butylphosphino) biphenyl in 10 ml of toluene. After cooling to RT, the mixture was diluted with ether. The suspension was filtered under vacuum. decalite and the filtrate was evaporated. The residue was purified on silica, eluting with a gradient of heptane / EtOAc. the title compound was obtained after evaporation. (b) 1- (3-Fluoro-4-trifluoromethyl-phenyl) -piperazine.

Tratou-sé uma mistura de 2,87 mmole do éster terc-butílico do ácido 4-(3-fluoro-4-trifluorometil-fenil)-p.iperazino-l-carboxílico, no seio de 10 ml de diclorometa- 127 no., com .14,4. mirtole. de ácido trifluoroacético. e fez-se. o refluxo durante 3 horas.· Concentrou-se a mistura, e tratou-se com 10 mL de água,· NaOH e ex'traiu-se com diclorometano. Secaram-se as fases orgânicas combinadas sobre MgSOa e evaporou-se, para. sè obter o composto . do título 5.1. EM (m/e) : 249,2 (MH+, 100 %) ·A mixture of 2.87 mmol of 4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester in 10 mL of dichloromethane was treated with. , with .14.4. mytole. of trifluoroacetic acid. and it was done. The mixture was concentrated, treated with water (10 mL), NaOH and extracted with dichloromethane. The combined organic phases were dried over MgSOâ, "and evaporated to dryness. to obtain the compound. of Title 5.1. MS (m / e): 249.2 (MH +, 100%)

Exemplo 5.2Example 5.2

Preparação de 2-piperazin-l-il-5-trifiuorometil-benzoni-triloPreparation of 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile

Preparou-se o composto em analogia com o composto 5.1, a partir de 2-cloro-5-trifluorQmetil-benzonitrilo (patente de invenção alemã DE 2550262) . EM (m/e) : 256,0 )(MH“, 100 %)The compound was prepared in analogy to compound 5.1 from 2-chloro-5-trifluoromethyl-benzonitrile (German patent DE 2550262). MS (m / e): 256.0 (MH +, 100%)

Exemplo 5.3Example 5.3

Preparação de 1-(2,3-difluoro-4-metano-sulfonil-fenil)-pi-perazina &quot;Preparation of 1- (2,3-Difluoro-4-methanesulfonyl-phenyl) -piperazine &quot;

Preparou-se o composto em analogia com- o composto 2.20, a partir de cloreto. , de 2,3,4-t.rifluoro-benzeno-sulfonilo. (comercial) . EM (m/e) : 277,2 (MH+, 100 %}The compound was prepared in analogy to compound 2.20, from chloride. , of 2,3,4-trifluorobenzenesulfonyl. (commercial). MS (m / e): 277.2 (MH +, 100%)

Exemplo 5.4Example 5.4

Preparação de 1-(2-fluoro-4-metil-fenil)-piperazinaPreparation of 1- (2-fluoro-4-methyl-phenyl) -piperazine

Preparou-se o composto em analogia com o composto 1.1, a partir 4-bromo.-3-f luorotolueno (comercial). EM (m/e): 195,3 (MH+, 100 %) ·' 128The compound was prepared in analogy to compound 1.1 from 4-bromo-3-fluorotoluene (commercial). MS (m / e): 195.3 (MH +, 100%).

Exemplo 5.5Example 5.5

Preparação de 1- (3-fliioro“5-trifluoromet:il-piridíii-2-il&gt; piperazinaPreparation of 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) piperazine

Preparou-sé, o composto em analogia com o composto 2.7, a partir de '2,3-difluoro-5-trifluorometil-piridina (patente de invenção europeia EP 0104715)·. EM- (m/e).: 250,2 (MH+, .100 %)The compound in analogy to compound 2.7 was prepared from 2,3-difluoro-5-trifluoromethyl-pyridine (EP 0104715).  € ƒâ € ƒâ € ƒMS (m / e): 250.2 (MH +, 100%)

Exemplo 5.6Example 5.6

Preparação do ácido S-metano-sulfonil-Z-((S)-2,2,2-trifluó ro-l-metil-etoxi)-benzóico (a) Éster metillco do ácido'. rac-5-metano-sulfonil-2-. (2,2,2-triflúoro-l-metil-etoxi)-benzóicoPreparation of S-methanesulfonyl-Z - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (a) rac-5-methanesulfonyl-2-. (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid

Agitou-se a 8C °C, durante 48 horas, uma mistura de 21, 7 mmole de éster; mctílico do ácido 2-hidroxi-5-netano-sulfonil-benzóico [68029-77-6], 32,5 mmole do éster 2,2,2-trifluoro-l-metil-etílico do ácido trifluoro-metano-sulfó-nico [212556-43-9], 43,4 mmole de carbonato de potássio, r.o seio dè 87 mL de DMF. Depois de se arrefecer para a TA, concentrou-se a mistura in vácuo, recolheu-se em água e agitou-se durante 1 hora'. A filtração originou o composto do titulo. '.' ' (b) Éster metilico do' ácido 5-metano-sulfonil-2-((S)-2,2,2-trifluorc-l-metil-etoxi) -benzoicó'A mixture of 21.7 mmol of ester was stirred at 80 ° C for 48 hours; 2-hydroxy-5-methanesulfonyl-benzoic acid [68029-77-6], 32.5 mmol of trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9], 43.4 mmol of potassium carbonate, with 87 mL of DMF. After cooling to RT, the mixture was concentrated in vacuo, taken up in water and stirred for 1 hour. Filtration gave the title compound. '.' (b) 5-Methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid methyl ester

Obteve-se o composto do título por separação do éster, metilico do ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-benzóico por CLER quirálica (Chiralcel OD, 129 etanòl a 15 %/heptano, fluxo de 35 ir.L, 220 nm, tempo de retenção: 86 minutos). (c) Ácido- 5-metano-sulfonil-2^ ( (S) -2,2-, 2-trifluoro-l-metil-etoxi) -benzóicoThe title compound was obtained by separation of rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid methyl ester with chiral HPLC (Chiralcel OD, 129 15% ethanolic / heptane, 35 æL flow, 220 nm, retention time: 86 minutes). (c) 5-Methanesulfonyl-2 ((S) -2,2-, 2-trifluoro-1-methyl-ethoxy) -benzoic acid

Preparou-se o composto ém analogia com o composto 2.10 . (b), a partir do éster metilico do ácido.S-metano-sulfonil-2-( (S) ,-2,2,2-tri.fruoro-l-metil-etoxi)-benzóico. EM', (m/e).: 311,0 (M-H, 100 %)The compound was prepared by analogy with compound 2.10. (b) from S-methanesulfonyl-2 - ((S), -2,2,2-trifruoro-1-methyl-ethoxy) -benzoic acid methyl ester. MS (m / e): 311.0 (M-H, 100%)

Exemplo 5.7Example 5.7

Preparação do ácido 5-metano-sulfonil-2- ((R) -2,2,2“triflTio-ro-l-metil-etoxi)-benzóico (a) ÉsLer metilico, do ácido. 5-metano-sulfonil-2-((R)-,2,2&quot;,2-trifluoro-l-metil-etoxi) -benzóico .Preparation of 5-Methanesulfonyl-2 - ((R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (a) 5-methanesulfonyl-2 - ((R) -, 2,2 &quot;, 2-trifluoro-1-methyl-ethoxy) -benzoic acid.

Obteve-se o composto do titulo; por separação do. éster, metilico. do ácido rac-5-metanc-sulfon.i 1.-2- (2,2,2-trifluoro-1-metiletoxi)-benzóico por CLER quirálica (Chiralcel OD, étanol a 15 %/heptano, fluxo de 35 mL, 220 nm, témpo de retenção: 74 minutos). (b) Ácido 5-metano-sulfonil-2-((R)-2,2,2-trifluoro-l-me-til-etoxi) -benzóicoThe title compound was obtained; by separation of the. ester, methyl. (Chiralcel OD, 15% ethanol / heptane, 35 ml flow, 5-methanesulfonyl-2- (2,2,2-trifluoro-1-methylethoxy) benzoic acid, 220 nm, retention time: 74 minutes). (b) 5-Methanesulfonyl-2 - ((R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid

Preparou-se o composto em analogia com o composto 2.10 (b) , a partir do éster metilico do ácido 5-metano-sulfor.ii-2-('(R)-2,2,2-trifluoro-l-metil-etoxi)-benzóico. EM (m/e) : .311,0 {M-H, ICC %) . 130The compound was prepared in analogy to compound 2.10 (b) from 5-methanesulfonyl-2 - ((R) -2,2,2-trifluoro-1-methyl- ethoxy) -benzoic acid. MS (m / e): .311.0 (M-H, ICC%). 130

Exemplo 5.8Example 5.8

Preparação de 2-cloro-4-piperazin-l-il-benzonitriloPreparation of 2-chloro-4-piperazin-1-yl-benzonitrile

Aqueceu-se durante 1 hora, a 85 °C, uma mistura de 7,0 mmole de 2-cloro-4-fluorobenzonitrilo (comercial), 10,5 mmole de piperazina, no seio de 4 mL de N,N-dimetil-acetamida. Depois de se arrefecer para a TA e da evaporação in vacuo, diluiu-se a mistura com diclorometano e purificou-se em silica, eluindo-se com um gradiente de diclorometano/MeOH, para se obter, após evaporação, o composto do titulo. EM (m/e): 222,1 (MH+, 100 %)A mixture of 7.0 mmol of 2-chloro-4-fluorobenzonitrile (commercial), 10.5 mmol of piperazine in 4 mL of N, N-dimethylformamide was heated at 85øC for 1 hour. acetamide. After cooling to RT and evaporation in vacuo, the mixture was diluted with dichloromethane and purified on silica, eluting with a dichloromethane / MeOH gradient to give, after evaporation, the title compound. MS (m / e): 222.1 (MH +, 100%)

Exemplo 5.9Example 5.9

Preparação de 1-(2-fluoro-4-piperazin~l-il-fen.il)-etanonaPreparation of 1- (2-fluoro-4-piperazin-1-yl-phenyl) -ethanone

Preparou-se o composto em analogia com o composto 5.8, a partir de 2,4-difluoroacetofenona (comercial). EM (m/e): 223,2 (M-H, 1.00 %)The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m / e): 223.2 (M-H, 1.00%)

Exemplo 5.10Example 5.10

Preparação de 1-(3-fluoro-4-metano-sulfonil-fenil)-piperazinaPreparation of 1- (3-fluoro-4-methanesulfonyl-phenyl) -piperazine

Preparou-se o composto em analogia com o composto 2.20, a partir de cloreto de 2,4-difluorobenzeno-sulfonilo (comercial). EM (m/e): 259,1 (MH+, 100 %)The compound was prepared in analogy to compound 2.20 from 2,4-difluorobenzenesulfonyl chloride (commercial). MS (m / e): 259.1 (MH +, 100%)

Exemplo 5.11Example 5.11

Preparação de 1-(4-fluoro-2-piperazin-l-il-fenil)-etanona 131Preparation of 1- (4-fluoro-2-piperazin-1-yl-phenyl) -ethanone

Preparou-se o composto em analogia com o composto 5.8, a partir de 2,4-difluoroacetofenona (comercial). EM (m/e): 223,2 &lt;M-H, 100 %)The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m / e): 223.2 &lt; M-H, 100%)

Exemplo 5.12Example 5.12

Preparação do ácido 6-isopropoxi-isoftalâmicoPreparation of 6-isopropoxy-isophthalamic acid

Preparou-se o composto em analogia com o composto 2.10, a partir do éster metilico do ácido 6-hidroxi-isoftalâmico [89366-34-7]. EM (m/e): 222,1 (M-H, 100 %)The compound was prepared in analogy to compound 2.10 from 6-hydroxy-isophthalamic acid methyl ester [89366-34-7]. MS (m / e): 222.1 (M-H, 100%)

Exemplo 5.13Example 5.13

Preparação do ácido 5-etanO“Sulfonil“2-isopropoxi-benzóico (a) Éster metilico do ácido 5-etano-sulfonil-2-hidroxi-benzóicoPreparation of 5-ethanO "Sulphonyl" 2-isopropoxy-benzoic acid (a) 5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester

Preparou-se o composto em analogia com o composto 2.20 (b), a partir do ácido 2-hidroxi-5-sulfino-benzóico [19479-88-0] e iodeto de etilo. (b) Ácido 5-etano-sulfonil-2-isopropoxi-benzóico . Preparou-se o composto em analogia com o composto 2.10, a partir do éster metilico do ácido 5-etano-sulfonil-2-hidroxi-benzóico. EM (m/e): 271,1 (M-H, 100 %)The compound was prepared in analogy to compound 2.20 (b) from 2-hydroxy-5-sulfino-benzoic acid [19479-88-0] and ethyl iodide. (b) 5-Ethanesulfonyl-2-isopropoxy-benzoic acid. The compound was prepared in analogy to compound 2.10 from 5-ethanesulfonyl-2-hydroxy-benzoic acid methyl ester. MS (m / e): 271.1 (M-H, 100%)

Exemplo 5.14Example 5.14

Preparação de 1-(4-difluorometil-2-fluoro-fenil)-piperazina (a) l-Cloro-4-difluorometil-2-fluoro-benzeno 132Preparation of 1- (4-difluoromethyl-2-fluoro-phenyl) -piperazine (a) 1-Chloro-4-difluoromethyl-2-fluoro-benzene

Dissolveu-se 24,7 mmole de 4-cloro-3-fluoroben-zaldeído, no seio de DAST (5,1 ml), em atmosfera de azoto. Agitou-se a mistura à temperatura ambiente, durante 3 horas, a 50 °C, durante 2 horas e depois à temperatura ambiente, durante 65 horas. Adicionou-se a solução, gota a gota, a uma solução saturada de bicarbonato (150 mL) , com arrefecimento. Extraiu-se a camada aquosa 3 vezes com acetato de etilo. Secaram-se os extractos combinados sobre Na2S04, filtrou-se e eliminou-se o dissolvente in vacuo. Purificou-se o resíduo em sílica, eluindo-se com heptano, para se obter, após evaporação, o composto do título. (b) 1-(4-Difluorometil-2-fluoro-fenil)-piperazina24.7 mmol of 4-chloro-3-fluorobenzaldehyde was dissolved in DAST (5.1 mL) under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 3 hours at 50 ° C for 2 hours and then at room temperature for 65 hours. The solution was added dropwise to saturated bicarbonate solution (150 mL) with cooling. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified on silica eluting with heptane to afford, after evaporation, the title compound. (b) 1- (4-Difluoromethyl-2-fluoro-phenyl) -piperazine

Preparou-se o composto em analogia com o composto 1.1, a partir de l-cloro-4-difluorometil-2-fluoro-benzeno. EM (m/e) : 231,2 (M+H+, 100 %)The compound was prepared in analogy to compound 1.1 from 1-chloro-4-difluoromethyl-2-fluoro-benzene. MS (m / e): 231.2 (M + H +, 100%)

Exemplo 5.15Example 5.15

Preparação de 1-(6-trifluorometil-piridin-3-il)-piperazinaPreparation of 1- (6-trifluoromethyl-pyridin-3-yl) -piperazine

Preparôu-se o composto em analogia com o composto 1.1, a partir de 5-bromo-2-trifluorometil-piridina [436799-32-5]. EM (m/e): 232,1 (M+H+, 100 %)The compound was prepared in analogy to compound 1.1 from 5-bromo-2-trifluoromethyl-pyridine [436799-32-5]. MS (m / e): 232.1 (M + H +, 100%)

Exemplo 5.16Example 5.16

Preparação do éster etílico do ácido 3-fluoro-4-piperazin-1-il-benzóicoPreparation of 3-fluoro-4-piperazin-1-yl-benzoic acid ethyl ester

Preparou-se o composto em analogia com o composto 5.8, a partir de 3,4-difluorobenzoato de etilo (comercial) . EM (m/e): 253,2 (M+H+, 100 %) 133The compound was prepared in analogy to compound 5.8 from ethyl (commercial) 3,4-difluorobenzoate. MS (m / e): 253.2 (M + H +, 100%)

II

Exemplo 5.17Example 5.17

Preparação de 1-(2-trifluorometil-piridin-4-il)-piperazinaPreparation of 1- (2-trifluoromethyl-pyridin-4-yl) -piperazine

Pode preparar-se o composto a partir de 1-óxido de 4-nitro-2-trifluorometil-piridina [147149-97-1], em analogia com o processo utilizado para a preparação de 4-bromo-2-metil-6-trif luorometil-piridina [61557 9-7.8-1] (patente de invenção WO 03087056). EM (m/e) 227 (M+H+, 100 %)The compound can be prepared from 4-nitro-2-trifluoromethylpyridine 1-oxide [147149-97-1], analogously to the procedure used for the preparation of 4-bromo-2-methyl-6- trifluoromethyl-pyridine [61557-9-7.8-1] (WO 03087056). MS (m / e) 227 (M + H +, 100%)

Exemplo 5.18Example 5.18

Preparação de 1-(6-metil-piridin-3-il)-piperazinaPreparation of 1- (6-methyl-pyridin-3-yl) -piperazine

Preparou-se o composto,em analogia com o composto 1.1, a partir de 5'-bromo-2-metil-piridina (comercial) . EM (m/e) : 178,1 (M+H+, 100 %)The compound, in analogy to compound 1.1, was prepared from 5'-bromo-2-methyl-pyridine (commercial). MS (m / e): 178.1 (M + H +, 100%)

Em analogia com o exemplo 5, prepararam-se os compostos 363 a 4 61 do quadro que se segue, a partir de derivados de ácido e derivados de piperazina:In analogy to example 5, compounds 363 to 460 of the following table were prepared from acid derivatives and piperazine derivatives:

Exemp. N°. Nome Sistemático Materiais Iniciais EM encont. (MH*) 363 2-[4- (2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin- . 1-il]-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluoròmetil-benzonitrilo (conçiosto 5.2) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 496,3 364 4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-1-il]-2-trifluorometíl-benzonitrilo 4-piperazin-l“il-2-trifluorometil-benzonitrilo (patente de invenção WO 0017163) e ácido 2-isopropoxi-5-metano~ sulfonil-benzóico (composto 1.2) 496,3 365 l-{4-[4-{2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2- 1-(4-piperazín-l-il-2-trifluorometil-fenil)-etanona (patente de invenção WO 0210277) 513,4 134 trlfluorometil-fenil}-etanona e ácido 2-isoproxi-5-metano-. sulfonil-benzóico (composto 1,2) 366 2-cloro-4-[4- (2-isopropoxi-5-metano-sulfonil-benzoil) -piperazin-l-il]-benzonitrilo 2-cloro-4-piperazin-l-il-benzonitrilo (composto 5.8) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 462,3 3 67 l-{2-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -fenil}-etanona 1-(2-fluoro-4-piperazin-l-il-fenil)-etanona (composto 5.9) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 463, 4 368 [4-(3-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(3-fluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.10) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 499, 3 369 l-{4-[4-(2- ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -2-fluoro-fenil}-etanona 1-(2-fluoro-4-piperazin-l-il-fenil)-etanona (composto 5.9) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 475,4 370 (2-ciclopropilmetoxi-5-raetano-sulfonil-fenil)-[4-(3-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(3-fluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.10} e ácido 2-ciclopropilme-toxi-5-metano-sulfonil-benzóico (composto 1.4) 511,4 371 [4-(3-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - (2-isobutoxi-5-metano-sulfonil-fenil)-metanona 1-(3-fluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.10) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 513,4 372 l-{2-fluoro-4-[4-(2-isobu-toxi-5-metano-sulfonil-benzoil}-piperazin-l-il]-fenil}-etanona 1-(2-fluoro-4-piperazin-l-il-fenil)-etanona (composto 5.9) e ácido 2-isobutoxi-5-metano-sul-fonil-benzóico (composto 1.3) 477,3 373 2-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil) -^piperazin-l-il]-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluo~ rometil-benzonitrilo (composto 5.2) e ácido 2-ciclopentiloxi-5-metano-sulfonil-ben z ói co (composto 1.6) 522,4 374' 2-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluorometil-benzonitrilo (composto 5.2) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 508, 6 375 2-[4-(2-isobutoxi-5-metano- 2-piperazin-l-il-5- 510,6 135 sulfonil-benzoil)-piperazin-1-il]-5-trifluorometil-benzonitrilo trifluorometil-benzonitrilo (composto 5.2) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 376 2— {4— [5'-metano-sulfonil-2-(2,2,2-trifluoro-etòxi)-benzoil]-piperazin-l-il}-5-trifluorometil-benzonitrilo 2-piperazin-l-il-5-trifluorometil-benzonitrilo (composto 5.2) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóíco (composto 1.5) 536,5 377 rac- [4- (3-fluoro-4-itietano-sulfonil-fenil}-piperazin-1-11]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil] -metanona 1-(3-£luoro-4-metano-sulfonil-fenil)-piperazina (composto 5.10) a ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 3.1) 553,2 37 8 . rac-l-(2-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil]-piperazin-l-il)-fenil)-etanona 1-(2-£luoro-4-piperazin-l-il-fenil)-etanona (composto 5.9) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 517,4 379 1-{4-fluoro-2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -fenil}-etanona 1-(4-fluoro-2-piperazin-l-il-fenil)-etanona (composto 5.11) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 463,4 380 3-[4-(2-fluoro-4-trifluorometil-fenil)-piperazino-l-carbonil]-4-isopropoxi-benzamida 1-(2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 6-isopropoxi-isoftalâmico (composto 5.12) 454,6 381 4-isopropoxi-3-[4-(4-trifluorometil-fenil) -piperazino-l-carbonil]-benzamida 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 6-isopropoxi-isoftalâmico (composto 5.12) 436,4 382 3-[4-(3-fluoro-4-trifluorometil-fenil)-piperazino-l-carbonil]-4-isopropoxi-benzami da 1-(3-fluoro-4-trifluorometil-fenil)-piperazina (composto 5.1) e ácido 6-isopropoxi-isoftalâmico (composto 5.12) 454, 6 383 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-4-isopropoxi-benzamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 6-isopropoxi-isoftalâmico (composto 5.12) 464,4 384 3-[4-(2-ciano-4-trifluorometil-fenil)-piperazino-l-carbonil]-4-isopropoxi-benzamida 2-piperazin-1-i1-5-trifluorome-til-benzonitrilo (composto 5.2) e ácido 6-isopropoxi-isoftalâ-mico (composto 5.12) 461,4 385 3-14-(4-ciano-fenil)- 4-piperazin-l-il-benzonitrilo 393,2 136 piperazino-l-carbonil]-4-isopropoxi-benzamida (comercial) e ácido 6-iSopro-poxi-isoftalâmico (composto 5.12) 386 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil] -4-isopropoxi-benzamida 3-fluoro-4-pipe ra zin-1-i1-ben-zonitrilo (patente de invenção WO 9625414) e ácido 6-isopro-poxi-isoftalâmico (composto 5.12) 411,4 387 3-[4-(4-ciano~3-fluoro-fenil)-piperazino-l-carbonil) -4-isopropoxi- benzamida 2-fluoro-4-piperazin-l-il-benm-zonitrilo (patente de invenção WO 9808835) e ácido 6-isopro-poxi-isoftalâmico (composto 5.12) 411,4 388 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-l-carbonil] -4-isopropoxi-benzamida' 1-(3-£luoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690.) e ácido 6-isopropoxi-isoftalâmico (composto 5.12) 428,6 389 [4- (2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(2,3-difluoro-4-metano-sul-fonil-fenil)-piperazina (composto· 5.3) e ácido 2-isopro-poxi-5-inetano-sulfonil-benzóico (composto 1.2) 517,4 390 (5-etano-sulfonil-2-isopropoxi-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 5“ etano-sulfonil-2-isopropoxi-benzóico (composto 5.13) 485,5 391 (5-etano-sulfonil-2-isopropoxi-fenil)-[4-(2-fluo ro-4-met ano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-etano-sulfonil-2-iso-propoxi-benzóico. (composto -5.13) 513,4 392 4-4- (5-etano-sulf oni.1-2-isopropoxi-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l-il-ben-zonitrilo (patente de invenção WO 9625414) e ácido 5-etano-sulf onil-2-isopropoxi-benzóico (composto 5.13) 460,5 393 (5-etano-sulfonil-2-isopropoxi-fenil)-[4-(2-fluoro-4-t.rif luorometil-fenil) -piperazin-l-il] -metanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 5-etano-sulfonil-2-isopropoxi-benzôico (composto 5.13) 503,3 137 394 [4-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - (5-etano-sulfonil-2-isopropoxi-fenil)-metanona 1- (2,3-difluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.3) e ácido 5-etano-sulfonil-2-isopropoxi-benzóico (composto 5.13) 531,3 395 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(2,3difluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-metanona 1- (2,3-difluoro-4-metano-sulfonil-fenil)-piperazina (composto 5.3) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 542,1 396 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4- (2,3-difluoro-4-metanor sulfonil-fenil)-piperazin-1-il]-metanona 1- (2., 3-difluoro-4-metano-sulfonil-fenil)-metano-sulfonil-fenil)-piperazina (composto 5.3) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 529,3 397 [4-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1- (2,3-difluoro-4-metano-sulfo-nil-fenil)-piperazina (composto 5.3) e ácido 5-metano-sulfonil- 2- (2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 557,2 398 rac-[4-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-fenil]-metanona 1-(2,3-difluoro-4-metano-sulfo-nil-fenil)-piperazina (composto 5.3) e ácido rac-5-metano-sul-fonil-2-(2,2,2-trifluoro-l-me-til-etoxi) -benzóico (composto 3.1) 571,3 399 [4-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - (5-metano-sulfonil-2-trifluorometoxi-fenil)-metanona 1- (2,3-difluoro-4-metano-sulfo-nil-fenil)-piperazina (composto 5.3) e ácido 5-metano-sulfonil- 2- trifluorometoxi-benzóico (composto 2.15) 543,2 400 [4-(4-difluorometil-2-fluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(4-difluorometil-2-fluoro-fe-nil)-piperazina (composto 5.14) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 471,1 401 [4-(3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il)-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil)-metanona 1-(3-cloro-5-trifluorometil-piridin-2-il)-piperazina (comercial) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 546,3 402 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4- 1- (5-trifluorometil-piridin-piperazina (comercial) e ácido 512,4 138Exemp. No. Systematic Name Initial Materials EM Found. (MH +) 363 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-. 1-yl] -5-trifluoromethyl-benzonitrile 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5.2) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 496.3 364 4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-trifluoromethyl-benzonitrile 4-piperazin-1-yl-2-trifluoromethyl-benzonitrile (WO 0017163) and 2-isopropoxy-5-methanesulfonylbenzoic acid (compound 1.2) 496.3 365 1- {4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2- 1- (4-piperazin-1-yl-2-trifluoromethyl-phenyl) -ethanone (WO 0210277) 513.4134 trifluoromethyl-phenyl} -ethanone and 2-isoproxy-5-methano- 1-yl] -benzonitrile 2-chloro-4-piperazin-1-yl) -benzonitrile (compound 1.2) 366 2-Chloro-4- [4- (2-isopropoxy-5-methanesulfonyl- benzoyl) (compound 5.8) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 462.3367 1- {2-fluoro-4- [4- (2-isopropoxy-5-methane 1-yl] -phenyl} -ethanone 1- (2-fluoro-4-piperazin-1-yl-phenyl) -ethanone (compound 5.9) and 2-isopropoxy-5-methano- (4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone (Compound 5.10) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 499.336 {1- [4- (4-methanesulfonyl-phenyl) (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-phenyl} -ethanone 1- (2-fluoro-4-piperazin-1-yl-phenyl) -ethanone (compound 5.9) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 475.4 370 (2-cyclopropylmethoxy-5- 4- (3-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (3-fluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.10 ) and 2-cyclopropylmethoxy-5-methanesulfonylbenzoic acid (compound 1.4) 511.4 371 [4- (3-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (3-fluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.10) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3 ) 513.4 372 1- {2-fluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone 1- (2-fluoro 4-piperazin-1-yl-phenyl) -ethanone (compound 5.9) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) 477.3 373 2- [4- (2-cyclopentyloxy- 5-trifluoromethyl-benzonitrile (compound 5.2) and 2-cyclopentyloxy-5-methane-2-carboxylic acid (compound 5.2) (compound 1.6) 522.4 374 2- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] yl] -5-trifluoromethyl-benzonitrile 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5.2) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 508.66 2- [4- - (2-isobutoxy-5-methano-2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5.2) and 2-isobutoxy-5-methanesulfonylbenzoic acid (compound 1.3) 376 2- {4- [5'-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1- yl) -5-trifluoromethyl-benzonitrile 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile (compound 5.2) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 536.5377 rac- [4- (3-fluoro-4-ethethanesulfonyl-phenyl) -piperazin-1-11] - [5-methanesulfonyl-2- (2,2,2- methyl-ethoxy) -phenyl] -methanone 1- (3-fluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.10) to rac-5-methanesulfonyl- 2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 553.2378. rac-1- (2-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl) -phenyl] ) -ethanone (compound 5.9) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-phenyl- methyl-ethoxy) -benzoic acid (compound 3.1) 517.4 379 1- {4-fluoro-2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} - ethanone 1- (4-fluoro-2-piperazin-1-yl-phenyl) -ethanone (compound 5.11) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 463.4 380 3- [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzamide (compound 1.1) and 6-isopropoxy-isophthalamic acid (compound 5.12) 454.6 381 4-isopropoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzamide 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and (3-fluoro-4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzamide (compound 5.12) (compound 5.1) and 6-isopropoxy-isophthalamic acid (compound 5.12) 454, 633 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] ] -4-isopropoxy-benzamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 6-isopropoxy-isophthalamic acid (compound 5.12) 464.4384 3- [4- (2- cyano-4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzamide 2-piperazin-1-yl] -trifluoromethyl-benzonitrile (compound 5.2) and 6-isopropoxy-isophthalamic acid ( compound 5.12) 461.4 385 3-14- (4-cyano-phenyl) -4-piperazin-1-yl-benzonitrile 393.2 136 piperazine-1-carbonyl] -4-isopropoxy-benzamide (commercial) and (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzamide 3-fluoro-4-piperazin- 1-benzonitrile (WO 9625414) and 6-isopropoxy-isophthalamic acid (compound 5.12) 411.4387 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine- 1-carbonyl) -4-isopropoxybenzamide 2-fluoro-4-piperazin-1-ylbenzonitrile (WO 9808835) and 6-isopropoxy-isophthalamic acid (compound 5.12) 411.4388 3- [4- (4-acetyl- 2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 6-isopropoxy-isophthalamic acid (compound 5.12) 428.6 389 [4- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl- phenyl) -methanone 1- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazine (compound · 5.3) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) , 4 390 (5-ethanesulfonyl-2-isopropoxy-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-phenyl) -piperazine and 5-ethanesulfonyl-2-isopropoxy-benzoic acid (compound 5.13) 485.5 391 (5-ethanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-methanesulfonyl- -phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine commercial) and 5-ethanesulfonyl-2-iso-propoxy-benzoic acid. (compound -5.13) 513.4 392 4-4- (5-ethanesulfonyl-2-isopropoxy-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin- 1-yl-benzonitrile (WO 9625414) and 5-ethanesulfonyl-2-isopropoxy-benzoic acid (compound 5.13) 460.5393 (5-ethanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and 5-ethane 2-isopropoxy-benzoic acid (compound 5.13) 503.3 137 394 [4- (2,3-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (5-ethanesulfonyl- 2-isopropoxy-phenyl) -methanone 1- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and 5-ethanesulfonyl-2-isopropoxy-benzoic acid (compound 5.13) (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2,3- 4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid to 1.6) 542.1 396 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- ( 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 529.3 397 [ 4- (2,3-Difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 557.2 398 rac- [4- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and rac-5-methanesulfonyl- 2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 571.3 399 [4- (2,3-Difluoro-4-methanesulfonyl-phenyl) -piperazin- 1-yl] - (5-methanesulfonyl-2-trifluoromethoxy-phenyl) -met anion 1- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and 5-methanesulfonyl-2-trifluoromethoxy-benzoic acid (compound 2.15) 543.2 400 [4- (4-Difluoromethyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-Difluoromethyl-2-fluoro- piperazine (compound 5.14) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 471.1401 [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin- ) - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl) -methanone 1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 546.3 402 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4-l- (5-trifluoromethyl-pyridin-piperazine (commercial) and 512.48

I (5~trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (ccmnposto 1.5) 403 6-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]- piperazin-l-il}-nicotinonitrilo 6-piperazin-l-il-nicotinonitrilo (comercial) e ácido 5-metano-sulfonil-2-(2,2,2-tnfluoro-etoxi)-benzóico (composto 1.5) 469,3 404 6-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-ben2oil)-piperazin-l-il]-nicotinonitrilo 6-piperazin-l-il-nicotinonitrilo (comercial) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 441,4 405 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(5-trifluorometil-piridin-2-il)-piperázina (comercial) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 484,5 406 [4-(3-cloro-5-t ri fluo rometi1-piridin-2-il)-piperazin-l-il]-(2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-metanona 1-(3-cloro-5-trifluorometil-piridin-2-il)-piperazina (comercial) e ácido Z- ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 518,3 407 rac-[4- (3-cloro-5-trifluorometil,-piridin-2-il)-piperazinl-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona 1-(3-cloro-5-trifluorometil-piridin-2-il)-piperazina (comercial) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 560,3 408 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(5-trifluorometil-piridin-2- il)-piperazin-l-il]-metanona 1-(5-trifluorometil-piridin-2-il)-piperazina (comercial)· e· ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) ' 526,2 409 rac-6-{4-(5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil]-piperazin-l-il }-nicotinonitrilo 6-piperazin-l-il-nicotinonitrilo (comercial) e ácido rac-5-metano-suTfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 483,4 410' [4-(6-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-(2-ciclopropilmetoxi-5-metano-sulfoni-l-fenil)-metanona 1-(6-cloro-5-trifluorometil-piridin-2-il)-piperazina (patente de invenção WO 03097636) e ácido 2-ciclopropilmetoxi-5metano-sulfonil-benzóico (composto 1.4) 518,3 411 6-[4-(2-ciclopentiloxi-5- 6-piperazin-l-il-nicotinonitrilo 455,5 139 metano-sulfonil-benzoil) -piperazin-l-il]-nicotinonitrilo (comercial) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 412 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-(4-(5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(5-trifluorometil-piridin-2-il)-piperazina (comercial) e ácido 2-ciclopentiÍoxi-5-metano~ sulfonil-benzóico (composto 1.6) 498,3 413 [4- (3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-(2-ciclopentiloxi-5-metano-sulfonilfenil)-metanona 1- (3-cloro-5-triflu.orom.etil-piridin-2-il)-piperazina (corciercial) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 532,3 414 [4- (6-cloro-5-trifluorometil-piriàin-2-il)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(6-cloro-5-trifluorometil-píridin-2-il}-piperazina (patente de invenção WO 03097636) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1,2) 506, 3 415 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(5-trifluorometil-piridin-2-il)-piperazina (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 472,2 416 6-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -nicotinonitrilo 6-piperazin-l-il-nicotinonitrilo (comercial) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico {composto 1.2) 429,5 417 [4-(3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(3-cloro-5-trifluorometil-piridin-2-il}-piperazina (comercial) e 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 506,3 418 rac-[4-(5-cloro-piridin~2~ il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-f enil], -metanona 1-(5-cloro-piridin-2-il)-piperazina (patente de invenção WO 01062751) e ácido rac-5-metano-sulfonil-2-(2,2,2-trif luoro-1-metil-etox.i) -benzóico (composto 3.1) 492,3 419 [4- (5-cloro-pirídin-2-il)-piperazin-l-il]-(2-ciclopentiloxi-5-metano-sulfonil-fenil)-metanona 1- (5-cloro-piridin-2-il)-piperazina (patente de invenção WO 01062751) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 464,3 420 [4-(5-cloro-piridin-2-il) -piperazin-l-il]-(2-ciclopropilmetoxi-5-metano- 1-(5-eloro-piridin-2-il)-piperazina (patente de invenção WO 01062751) e ácido 2- 450,4 140 sulfonilfen.il) -metanona ciclopropilmetoxi-5-metano-sulfonil-benzôico (composto 1.4) 421 [4-(5-cloro-piridin-2-il)-piperazin-l-il]-[5-metano-SUlfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1-(5-cloro-piridin-2-il)-piperazina (patente de invenção WO 01062751) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico {composto 1.5) 478,2· 422 [4-(5-cloro-piridin-2-il)-piperazin-l-il]-(2-i s op ropoxi-5-met ano-sulfonil-fenil)-metanona 1-(5-cloro-piridin-2-il)-piperazina (patente de invenção WO 01062751) e ácido 2-isopropoxi-5-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 438,3 423 rac-[4-(6-cloro-piridazin-3-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona 3-cloro-6-piperazin-l-il-piridazina (patente de invenção WO 02030405) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 493,3 424 [4- (6-cloro-piridazin-3-il)-piperazin-l-il]-(2-ciclopentil.oxi-5-metano-sulfonil-fenil)-metanona 3-cloro-6-piperazin-l-il-piri-dazina (patente de invenção WO 02030405} e ácido 2-ciclopen-tiloxi-5-metano-sulfonil- benzóico (composto 1.6) 465,4 425 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(6-trifluorometil-piridin-3-il)-piperazin-l-il]-metanona 1-(6-trifluorometil-piridín-3-il)-piperazina (composto 5.15) e ácido 2-isopropoxi-5-metano-sulfonil-benzóíco (composto 1.2) 472,2 426 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(6-trifluorometil-piridin-3-il) -piperazin.-l-il] -metanona 1-(6-trifluorometil-piridin-3-il)-piperazina (composto 5.15) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 512,4 427 rac-[5-metano-sulfonil-2-(2,2,2-trifluoró-l-metil-etoxi)-fenil]-[4-(6-trifluorometil-piridin-3-il)-piperazin-l-il]-metanona 1-(6-trifluorometil-piridin-3-il)-piperazina (composto 5.15) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 526,2 428 éster etílico do ácido 3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzóico éster etílico do ácido 3-fluo-ro-4-piperazin-l-il-benzóicò (composto 5.16} e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 493,4 429 [4-(5-bromo-piridin-2-il)-piperazin-l-il]-(2- 1-(5-bromo-piridin-2-il)-piperazina (patente de invenção | 482,4 ? 141 isopropoxi-5-metano-sulfonil-fenil)-metanona WO 9534555} e ácido 2-isopropoxi—5-metano-sulfonil-benzóico (composto 1.2) 430 (2-ciclopentiloxi-5-metano-sulfonil-metano-sulfonil-fenil)-[4-(6-trifluorometil-piridin-3-il)-piperazin-1-il]-metanona 1-(6-trifluorometil-piridin-3-il)-piperazina (composto 5.15)· e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 498,3 431 (2-ciclopropilmetoxl-5-metano-sulfonil-fenil)-[4-(6-trifluorometil-pirldin-3-il)-piperazin-l-il]-metanona 1- (6-trifluorometil-piridin-3- . il)-piperazina (composto 5.15) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 484,5 432 4-[4-(5-bromo-piridin-2-il)-piperazin-l-il] - [5-metano?-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1-(5-bromo-piridin-2-il)-piperazina (patente de invenção WO 9534555) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 522,2 433. [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil] -[4-(2- trifluorometil-piridin-4-il)-piperazin-l-il]-metanona 1- (2-tri.fluorometil-piridin-4-il)-piperazina (composto 5.17) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 512,4 434 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(2-trifluorometil-piridin-4-il)-piperazin-l-il]-metanona 1-(2-trifluorometil-piridin-4-il)-piperazina (composto 5.17) e ácido 2-isopropoxi-5~metano-sulfonil-benzóico (composto 1.2) 472,2 435 rac-[4-(5-bromo-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-metanona 1-(5-bromo-piridin-2-il)-piperazina (patente de invenção WO 9534555) e ácido rac-5-raetano-sulfoni1-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 536,3 436 [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 530,3 437 [4-(3-fluoro-5-trifluorometil-piridin-2-ilj-piperazin-l-il]-(2- 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) é ácido 2- 490,4 142 isopropoxi-5-metano-sulfonil-fenil)-metanona isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 438 rac-[4-(3-fluoro-5-trifluorometil-piridin 2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) fenil]-metanona 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) e ácido rac-5-metano-sulfonil-2-(2,2,2-triflu.oro-1-metil-etoxi) -benzóico (composto 3.1) 544,3 439 (2-c ic1opentiloxi-5-met ano-sulfonil-fenil)-[4-(3-fluoro-5-trifluorometil-pirldin-2-il)-piperazin-1- il]-metanona 1-(3-fluoro-5~trifluorometil-piridin-2-il)-piperazina (com-, posto 5.5) e ácido 2-ciclopen-tiloxi-5-metano-sulfonil-ben-zóico (composto 1.6) 516,4 440 {2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -metanona 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) e ácido.2-ciclopro-pilme t oxi-5-metano-sulfoni1-benzóico (composto 1.4) 502,3 441 rac-[5-metano-sulfonil-2- (2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(2-tri-fluorometil-piridin-4-il)-piperazin-l-il]-metanona 1-(2-trifluorometil-piridin-4-il)-piperazina (composto 5.17) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 526,2 442 {5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi) -fenil].- [4-(6-metil-piridin-3-il) -piperazin-l-il]-metanona 1-(6-metil-piridin-3-il)-' piperazina (composto 5.18) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5} 458,4 443 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(6-metil-piridin-3-il)-piperazin-l-il] -metanona 1-(6-metil-piridin-3-il)-piperazina (composto 5.18) e ácido 2-isopropoxi-5-metano— sulfonil-benzóico (composto 1.2) 418,3 444 (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(S-metil-piridin-3-il)-piperazin-l-il] -metanona 1-(6-metil-piridin-3-il)-piperazina (composto 5.18) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) ' 444,4 445 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(6-metil-piridin-3-il)-piperazin-l-il]-metanona 1-(6-metil-pirídin-3-il)-pipérazina (composto 5.18) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 430,5 446 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(5-metil-piridin-2-il)-piperazin-l-il]-metanona 1-(5-metil-piridin-2-il)-piperazina (patente de invenção WO 03032996) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro- 458,0 143 etoxi)-benzóico (composto 1.5) 447 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(5-metil-piridin-2-il) -piperazin-1-il]-metanona 1-(5-metil-piridin-2-il)-piperazina (patente de invenção WO 03032996) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 418,3 448 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(5-metilpiridin-2-il)-piperazin-l-il]-metanona 1-(5-metil-piridin-2-il)-piperazina (patente de invenção WO 03032996) e ácido 2-ciclopro-pilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 430,5 449 rao-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil]-[4-(5-metil-piridin-2-il)-piperazin-1-. il]-metanona 1-(5-metil-piridin-2-il)-piperazina (patente de invenção WO 03032996) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluora-cético) (composto 3.1) 472,3 450 rac- [5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(6-metil-piridin-3-il)-piperazin-1-il]-metanona 1-(6-metil-piridin-3-il-piperazina (composto.5.18) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 472,2 451 [5-metano-sulfonil-2-(2,2,2- trifluoro-etoxi)-fenil]-[4-(4-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(4-trifluorometil-piridin-2-il)-piperazina (patente de invenção WO 02002529) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 512,4 452 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(4-trífluorometil-piridin-2-il) ~piperazin-l'-il] -metanona 1-(4-trifluorometil-piridin-2-il)-piperazina (patente de invenção WO 02002529) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 472,3 453 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(4-trifluorometil-piridin-2-il)-piperazina (patente de invenção WO 02002529) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 486,2 454 [4-(2-fluoro-4-metano-sul-fonil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-((S)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.6) 570,4 (M+NH/) 455 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil- 1-(4-trifluorometil-piridin-l-(4-trifluorometil-piridin-2-il)- 526,0 144 etoxi)-fenil)-[4-(4-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona piperazina (patente de in-venção WO 02002529) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 456 [4-(2-fluoro-4-metano-sul-fonil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2- . ((R)-2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metano-sulfonil-2-((R)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.7) 570,4 &lt;M+NH4+) 457 (2-cíclopentiloxi-5-metano-sulfonil-fenil)-[4-(4-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(4-trifluorometil-piridin-2-il)-piperazina (patente de invenção WO 02002529) e ácido 2~ ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 498,2 458 (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(6-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona 1-(6-trifluorometil-piridln-2-il)-piperazina (patente de invenção europeia EP 462638) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 472,1 ' 459 rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil]-(4-(6- trifluorometil-piridin-2-il)-piperazin-l-il]-metanona . 1-(6-trifluorometil-piridin-2-il)-piperazina (patente de invenção europeia EP 462638) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 526,0 460 [5-metano-sulfonil-2-(2,2,2- . trifluoro-etoxi)-fenil]-[4-(6-trifluorometil- piridin-2-il)-piperazin-l-il]-metanona 1-(6-trifluorometil-piridin-2-il)-piperazina (patente de invenção europeia ΞΡ 462638) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 512,2 4 61 3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-pip.erazin-l-il] -benzaldeído 1- (4-difluórometil-2-fluoro-. fenil)-piperazina (composto 5.14) e ácido 2-isopropoxi-5-metano-sulfonil-benzólco (composto 1.2) 449,1(5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 5-Methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 4- [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl} -nicotinonitrile 6-piperazin-1-yl-nicotinonitrile (commercial) and 5- methanesulfonyl-2- (2,2,2-trifluoroethoxy) benzoic acid (compound 1.5) 469.3 404 6- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1- yl] -nicotinonitrile 6-piperazin-1-yl-nicotinonitrile (commercial) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 441.4 405 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - (4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone and 2-cyclopropylmethoxy-5- methanesulfonyl-benzoic acid (compound 1.4) 484.5 406 [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -piperazin-1-yl] - (2-cyclopropylmethoxy-5-methane sulfonyl-phenyl) -methanone 1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine (commercial ) and Z-cyclopropylmethoxy-5-methanesulfonylbenzoic acid (compound 1.4) 518.3 407 rac- [4- (3-chloro-5-trifluoromethyl, pyridin-2-yl) -piperazin-1-yl] - [ 5- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 560.3408 rac- [5-methanesulfonyl-2- (2- , 5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (5-trifluoromethyl-pyridin-2 (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1): 526.2409 rac-5-methanesulfonyl-2- 6- {4- (5-Methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -nicotinonitrile 6-piperazin-1-yl-nicotinonitrile (commercial) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 483.4 410 '[4- (6-chloro-5- trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - (2-cyclopropyl) ethoxy-5-methanesulfonyl-1-phenyl) -methanone 1- (6-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine (WO 03097636) and 2-cyclopropylmethoxy-5-methanesulfonyl- benzoyl) -piperazin-1-yl] -nicotinonitrile (Compound 1.4) 518.3 411 6- [4- (2-cyclopentyloxy-5-piperazin-1-yl-nicotinonitrile 455.5, 139 methanesulfonyl-benzoyl) commercial)) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 412 (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - (4- (5-trifluoromethyl-pyridin-2-yl) -piperazine 1-yl] -methanone (commercial) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 498.3 413 [4- (4-chlorophenyl) 3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - (2-cyclopentyloxy-5-methanesulfonylphenyl) -methanone 1- (3-chloro-5-trifluoromethyl- pyridin-2-yl) -piperazine (2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 532.3 414 [4- (6-chloro-5-trifluoromethyl- -piperazin-1-yl] - (2-isopropyl) oxy-5-methanesulfonyl-phenyl) -methanone 1- (6-chloro-5-trifluoromethyl-pyridin-2-yl} -piperazine (WO 03097636) and 2-isopropoxy-5-methanesulfonyl- (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (5-trifluoromethyl-pyridin-2-yl) -piperazine (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 472.2 416 6- [4- (2-isopropoxy-5-methane 1-yl] nicotinonitrile 6-piperazin-1-yl-nicotinonitrile (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 429.5 417 [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (3-chloro-5-trifluoromethyl-pyridine -2-yl} -piperazine (commercial) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 506.3868 rac- [4- (5-chloro-pyridin-2-yl) -piperazin-1 -yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl], -methanone 1- ( 2-yl) piperazine (WO 01062751) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) 1- (5-chloropyridin-2-yl) -piperazin-1-yl] - (2-cyclopentyloxy-5-methanesulfonyl-phenyl) -methanone 2-yl) -piperazine (WO 01062751) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 464.3 420 [4- (5-chloro-pyridin-2 yl) -piperazin-1-yl] - (2-cyclopropylmethoxy-5-methano-1- (5-chloro-pyridin-2-yl) -piperazine (WO 01062751) and 2-4,4,4- sulfonylphenyl) -methanone cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 421 [4- (5-chloro-pyridin-2-yl) -piperazin-1-yl] - [5-methano- - (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (5-chloro-pyridin-2-yl) -piperazine (WO 01062751) and 5-methanesulfonyl-2- 2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 478.2 · 422 [4- (5-chloro-pyridin-2-yl) -piperazin-1-yl] - (2- (5-chloro-pyridin-2-yl) -piperazine (WO 01062751) and 2-isopropoxy-5-isopropoxy-5-methanesulfonyl-2-isopropoxy-5-methanesulfonyl- (4-chloro-pyridazin-3-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-1-methyl-ethoxy) -phenyl] -methanone 3-chloro-6-piperazin-1-yl-pyridazine (WO 02030405) and rac-5-methanesulfonyl- 2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 493.3 424 [4- (6-chloro-pyridazin-3-yl) -piperazin-1-yl] - (2-cyclopentyl-oxy-5- 3-chloro-6-piperazin-1-yl-pyrazine (WO 02030405) and 2-cyclopentyloxy-5-methanesulfonylbenzoic acid (compound 1.6) 465.4 425 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6-trifluoromethyl- 3-yl) -piperazine (compound 5.15) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 472.2 426 [5-methanesulfonic acid 2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6-trifluoromethyl- pyridin-3-yl) -piperazine (compound 5.15) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 512.4 427 rac- [5- sulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6- 3-yl) piperazine (compound 5.15) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 2 428 3-Fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzoic acid ethyl ester 3-fluoro-4-piperazinic acid ethyl ester 1-yl-benzoic acid (compound 5.16) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 493.4 429 [4- (5-bromo-pyridin-2-yl) -piperazin-1- yl] - (2-1- (5-bromo-pyridin-2-yl) -piperazine (Patent of Invention | 482.4 &quot; (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone WO 9534555 and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 430 (2-cyclopentyloxy-5-methanesulfonyl-methanesulfonyl-phenyl ) - [4- (6-trifluoromethyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6-trifluoromethyl-pyridin-3-yl) -piperazine (compound 5.15) and 2-cyclopentyloxy -5-methanesulfonyl-benzoic acid (compound 1.6) 498.3 431 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyridin-3-yl) -piperazin- ] -methanone 1- (6-trifluoromethyl-pyridin-3-yl) -piperazine (compound 5.15) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 484.5 432 4- [4- 5-bromo-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (5-bromo pyridin-2-yl) -piperazine (WO 9534555) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 522.243. (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyridine n-4-yl) -piperazin-1-yl] -methanone 1- (2-trifluoromethyl-pyridin-4-yl) -piperazine (compound 5.17) and 5-methanesulfonyl-2- , 2-trifluoromethoxy) -benzoic acid (compound 1.5) 512.4434 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (2-trifluoromethyl-pyridin-4-yl) -piperazin-1- yl] -methanone 1- (2-trifluoromethyl-pyridin-4-yl) -piperazine (compound 5.17) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 472.2 435 rac- [4- 5-bromo-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -methanone 1- (5-bromo 2-yl) -piperazine (WO 9534555) and rac-5-methanesulfonyl-2-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) , 3,386 [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) - phenyl] -methanone 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5.5) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 530.3 437 [4- (3-fluoro-5-trifluoromethyl- 2-yl] -piperazin-1-yl] - (2-1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5.5) is 2 490.4 142 isopropoxy acid -5-methanesulfonyl-phenyl) -methanone isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 438 rac- [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl ] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) phenyl] -methanone 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine ( compound 5) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 544.3, 439 (2-cyclopentyloxy-5- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone yl) -piperazine (Compound 5.5) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 516.4440 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5.5) and 5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-1H-imidazol-2-yl) ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyridin-4-yl) -piperazin-1-yl] -methanone 1- (2-trifluoromethyl-pyridin-4-yl) -piperazine (compound 5.17) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 526.2442 (5-methanesulfonyl-2- 2-trifluoromethoxy) phenyl] - [4- (6-methyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6-methyl-pyridin-3-yl) 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 458.4 [4- (6-methyl-pyridin-3-yl) -piperazine (compound 5.18) and 2-isopropoxy-5- methanesulfonyl-benzoic acid (compound 1.2) 418.3 444 (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (S-methyl-pyridin-3-yl) -piperazin-1-yl] -methanone 1- (6-methyl-pyridin-3-yl) -piperazine (compound 5.18) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6): 444.4-445 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (6-methylpyridin-3-yl) - piperazin-1-yl] -methanone 1- (6-methyl-pyridin-3-yl) -piperazine (compound 5.18) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (5-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (5- methyl-pyridin-2-yl) -piperazine (WO 03032996) and 5-methanesulfonyl-2- (2,2,2-trifluoro-4,58,0,14-ethoxy) -benzoic acid (compound 1.5) 447 ( (5-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (5-methyl-pyridin-2-yl) -piperazine-2-carboxylic acid 2-isopropoxy-5-methanesulfonyl- (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (5-methylpyridin-2-yl) -piperazine -2-yl) -piperazin-1-yl] -methanone 1- (5-methyl-pyridin-2-yl) -piperazine (WO 03032996) and 2- 5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [1,2,4] triazolo [ 4- (5-methyl-pyridin-2-yl) -piperazin-1-one. yl] -methanone 1- (5-methyl-pyridin-2-yl) -piperazine (WO 03032996) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-acetic acid) ( Compound 3.1) 472.3 450 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-methyl-pyridin-3-yl ) -piperazin-1-yl] -methanone 1- (6-methylpyridin-3-yl-piperazine (compound.5.18) and rac-5-methanesulfonyl-2- (2,2,2- 1-methyl-ethoxy) -benzoic acid (compound 3.1) 472.2451 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (4-trifluoromethyl- 2-yl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-pyridin-2-yl) -piperazine (WO 02002529) and 5-methanesulfonyl- (4-trifluoromethyl-pyridin-2-yl) -piperazine-1-carboxylic acid (2-trifluoromethoxy-2-trifluoromethoxy- yl] -methanone 1- (4-trifluoromethyl-pyridin-2-yl) -piperazine (WO 02002529) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 472.3 453 (2- tert-butoxy-5-methyl (4-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-pyridin-2-yl) -piperazine 02002529) and 2-tert-butoxy-5-methanesulfonylbenzoic acid (compound 2.19) 486.2454 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (2-fluoro-4-methanesulfonyl- ) and 5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.6) 570.4 (M + NH 4) 455 rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-1- (4-trifluoromethylpyridin-1- (4-trifluoromethyl-pyridin-2-yl) (4-ethoxy) -phenyl) - [4- (4-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone piperazine (WO 012002529) and rac-5-methanesulfonyl -2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 456 [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (Commercial)) and 5- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine methanesulfonyl-2 - ((R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.7) 570.4 <M + NH4 +) 457 (2-Cyclopentyloxy- sulfonyl-phenyl) - [4- (4-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (4-trifluoromethyl-pyridin-2-yl) -piperazine (WO 02002529) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 498.2 458 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (6-trifluoromethyl-pyridin-2-yl) - piperazin-1-yl] -methanone 1- (6-trifluoromethyl-pyridin-2-yl) -piperazine (EP 462638) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) (4-Trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -piperazin- 1-yl] -methanone 1- (6-trifluoromethyl-pyridin-2-yl) -piperazine (EP 462638) and rac-5-methanesulfonic acid nyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 526.0 460 [5-methanesulfonyl-2- (2,2,2- trifluoro-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone 1- (6-trifluoromethyl-pyridin-2-yl) -piperazine (Patent of Invention European Patent ΞΡ 462638) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 512.2 4 61 3-fluoro-4- [4- (2-isopropoxy- 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzaldehyde 1- (4-difluoromethoxy-2-fluoro-phenyl) -piperazine (compound 5.14) and 2-isopropoxy-5-methanesulfonyl- (compound 1.2) 449.1

Exemplo 462Example 462

Preparação de rac- {4- [2-fltioro-4- (1-hidroxi-etil) -fenil] -pi-perazin-l-il}-&lt;2-isopropoxi-5“metano-sulfonilfenil) -me-tanona 145Preparation of rac- {4- [2-fluoro-4- (1-hydroxy-ethyl) -phenyl] -piperazin-1-yl} - &lt; 2-isopropoxy-5'-methanesulfonylphenyl) -methanone 145

Dissolveu-se 0,086 mmole de l-{3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-fe-níl}-etanona, no seio de 1 mL etanol e adicionou-se 0,26 mmole de boro-hidreto de sódio. Fez-se o refluxo da. mistura durante 40 minutos, arrefeceu-se para a temperatura ambiente, parou-se a reacção com água, acidificou-se com HC1 1 N e extraiu-se com acetato de etilo. Secaram-se os extractos orgânicos combinados sobre Na2S04, filtrou-se e eliminou-se o dissolvente in vacuo. Purificou-se o resíduo em siliça, eluindo-se com heptano/acetato de.etilo,, para se obter, após evaporação, o composto do título. EM (m/e) : 4.65,4 (M+H+, 100 %)0.086 mmol of 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone was dissolved in 1 mL ethanol and 0.26 mmol sodium borohydride was added. The reaction was refluxed. The mixture was stirred for 40 minutes, cooled to room temperature, quenched with water, acidified with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified silica, eluting with heptane / ethyl acetate, to give, after evaporation, the title compound. MS (m / e): 4.65,4 (M + H +, 100%)

Exemplo 463Example 463

Preparação de {4-[2-flúoro-4-(l-hidroxi^l-metil-efcil)-fe-nil]-piperazin-l-il}-(2-isopropoxi-5-metano-sulfonil-fe-nil)-meta-nona A uma solução de 0,173 mmole de l-{3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-fe-nil}-etanona, no seio de tetra-hidrofurano (2 mL) , adicionou-se, gota a gota, 0,190 mmole de uma solução de metil-lítio 1,6 M, no seio de éter, a -75 °C. Agitou-se a mistura 2 horas e depois deixou-se aquecer até 0 °C. Parou-se a reacção' com uma solução de NH4CI a 20 % e extraiu-se 3 vezes com acetato de etilo. Secaram-se os extractos orgânicos combinados sobre Na2S04, filtrou-se e eliminou-se o dissolvente in vacuo. Purificou-se o resíduo em sílica, eluindo-se com diclorometano/MeOH, para se obter, após evaporação, o composto do título. EM (m/e): 479,5 (M+H+, 100 %) 146Preparation of {4- [2-fluoro-4- (1-hydroxy-1-methyl-efcyl) -phenyl] -piperazin-1-yl} - (2-isopropoxy-5-methanesulfonyl- ) -methanone To a solution of 0.173 mmol of 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} - ethanone in tetrahydrofuran (2 mL) was added dropwise 0.190 mmol of a 1.6 M solution of methyl lithium in ether at -75 ° C. The mixture was stirred for 2 hours and then allowed to warm to 0 ° C. The reaction was quenched with 20% NH 4 Cl solution and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified on silica eluting with dichloromethane / MeOH to provide, after evaporation, the title compound. MS (m / e): 479.5 (M + H +, 100%)

Os exemplos 464-471 foram preparados por separação do material racémico por meio de CLER quirálica:Examples 464-471 were prepared by separation of the racemic material by chiral HPLC:

Exemp N°. Nome Sistemático Materiais Iniciais Condições de Separação PM encont. (MH*) 4 64 [5-metano-sulfonil-2-{{S ou R)-2,2,2-tri-fluoro-l-metil-etoxi)-fenil]-[4-(5-trifluorometil-piri-din-2-il)-piperazin-1-il]-metanona rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil] -trifluorometil-piridin-2-il)-piperazin-l-il]-metanona (exemplo 408) Chiralpak AD, isopropanol a 20 %/heptano, fluxo de 35 mL, 254 nm, 170. min. 525,8 (M) .465 [5-metano-sulfonil-2-((R ou S)-2,2,2-tri-fluoro-l-metil-etoxi)-fenil]-(4-(5-trifluorometil-piri-dln-2-11)-piperazin-1-il]-metanona rac- [5-metano-sulfonil-2(2,2,2-(reifluoro-l-metil-etoxi) -fenil]-[4-(5-1 ri fluorometi1-piridin-2-il)-piperazin-l-il] -metanona (exemplo 408) Chiralpak AD, isopropanol a 20 %/heptano, fluxo de 35 mL, 254 nm, 245 min. 525,3 (M) 466 [4-(2-fluoro-4-tri-fluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-((S ou R)-2,2,2-trifluoro-l-metil-etoxi) -fenil]-metanona rac-[4-(2-fluoro-4-trifluorometil-fenil}-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -fenil]-metanona (exemplo 302) Chiralpak AD, isopropanol a 25 %/heptano, fluxo de 35 mL, 220 nm, 141 min. 543,2 467 [4-(2-fluoro-4-tri-fluorometil-fenil)-piperazin-l-il]-[5-metáno-sulfonil-2-((R ou 5)-2,2,2-trifluo-ro-l-metil-etoxi)-fenil]-metanona rac-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona (exemplo 302) Chiralpak AD, isopropanol a 25 %/heptano, fluxo de 35 mL, 220 nm, 199 min. 543,2 468 [5-met ano-sulfoni1-2-((S ou R)-2,2,2-tri-fluoro-l-metil-etoxi)-fenil]-[4-(4-trifluorometil-fe-nil)-piperazin-l-il]-metanona rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il] -metanona (exemplo 301) Chiralpak AD, isopropanol a 25 %/heptano, fluxo de 35 mL, 220 nm, 197 min. 525,2 469 [5-metano-sulfonil-2-((R ou S)-2,2,2-tri-fluoro-l-metil-etoxi)- rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)^fenil]-[4- Chiralpak AD, isopropanol a 25 %/hèptano. 525,2 147 fen.il] - [4- (4- (4-trifluorometil- fluxo de 35 mL, trifluorometil-fe- fenil)-piperazin-l-il]- 220 ma, 280 nil)-piperazin-l-il]- metanona (exemplo 301) min. metanona 470 [4-(3-£luoro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-((S)-2,2,2-trifluoro-metil-etoxi)-fenil]-metanona rac-[4-(3—fluoro-5-trifluoronietil-pirídin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-1-metil-etoxi)-fenil] -metanona (exemplo 438) Chiralpak AD, isopropanol a 20 %/heptano, fluxo de 35 mL, 254 ma, 110 min. 471 [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-[5-( (R) -2,2,2-trifl.uoro-1-metil-etoxi)-fenil]-metanona rac-(4-{3-fluoro-5-triflnorometil-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi}-fenil]-metanona Chiralpak AD&gt; isopropanol a 20 %/h.eptano, .fluxo de 35 mL, 254 ma, 145 min. 544,0Exemp. Systematic Name Initial Materials Separation Conditions PM found. (MH +) 646 [5-methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl- pyrimidin-2-yl) -piperazin-1-yl] -methanone rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -trifluoromethyl-pyridine -2-yl) -piperazin-1-yl] -methanone (example 408) Chiralpak AD, 20% isopropanol / heptane, 35 mL flow, 254 nm, 170. min. 525.8 (M) .465 [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - (4- (5- trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone rac- [5-methanesulfonyl-2- (2,2,2- (reifluoro-1-methyl-ethoxy) -phenyl] - [ Chiralpak AD, 20% isopropanol / heptane, flow of 35 mL, 254 nm, 245 min 525 (MH +) , 3 (M), 466 [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S or R) 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone rac- [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl- , 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone (example 302) Chiralpak AD, 25% isopropanol / heptane, 35 mL flow, 220 nm, 141 min 543.2 467 [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((R or 5) -2,2,2-trifluoro-1-methyl (4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro- 1-methyl-ethoxy) -phenyl] -methanone (example 302) Chiralpak AD, 25% isopropanol / heptane, flow of 35 mL, 220 nm, 199 min. 543.2 468 [5-Methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethyl- 1-yl] -methanone rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin- ) -piperazin-1-yl] -methanone (example 301) Chiralpak AD, 25% isopropanol / heptane, 35 mL flow, 220 nm, 197 min. 525.2 469 [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) rac-5-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4-Chiralpak AD, 25% isopropanol / heptane. 5-phenyl-piperazin-1-yl] -2,2-a] pyrazin-1-yl] -2- (4-trifluoromethyl- yl] -methanone (example 301) min. methanone 470 [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro methyl-ethoxy) -phenyl] -methanone rac- [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone (example 438) Chiralpak AD, 20% isopropanol / heptane, 35 mL flow, 254 mg, 110 min. 471 [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5 (R) -2,2,2-trifluoro-1-methyl-ethoxy ) -phenyl] -methanone rac- (4- {3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-1-methyl-ethoxy} -phenyl] -methanone Chiralpak AD> 20% isopropanol / water, 35 mL flow, 254 mg, 145 min, 544.0

Exemplo 6.1Example 6.1

Preparação do ácido 2-isobutoxi“5-metilsulfamoil“benzóico (a) ' Ácido 5-cloro-sulfonil-2-hidroxi-benzóico A 3,26 mole do ácido cloro-sulfónico, a 0 °C, adicionou-se 652 mmole de ácido salicilico, em pequenas porções e deixou-se a mistura em agitação à TA, durante 1 hora, depois a 50 , °C, durante 1 hora e, finalmente, a 70 °C, durante 1 hora. Adicionou-se então a mistura, gota a gota, a 1.000 mL de água com gelo, com agitação e continuou-se a agitação durante mais 30 minutos. Recolheram-se, por filtração, os cristais brancos resultantes, lavou-se três vezes com água e depois secou-se in vacuo, a 45 °C, durante 16 horas, para se obter o composto do titulo. EM (m/e) : 236, 8 ( [{37C1}M-H] ; 33 %), .235, 0 ( [ {37Cl}M-H] ; 100 %) (b) Ácido 2-hidroxi-5-metilsulfamoil-benzóico 148 A 63 mmole do ácido 5-cloro-sulfoni.l-2-hidroxi-ben-zóico, no seio de 120 mL de diclorometano, à TA, adicionou-se, gota a gota, 317 mmole de metilamina (solução de etanol 8 M) e deixou-se a mistura em agitação, à TA, durante 1 hora. Concentrou-se depois a mistura in vacuo. Fez-se uma suspensão do resíduo numa solução aquosa de NaOH 1 M e extraiu-se 2 vezes com éter. Acidíficou-se a fase aquosa cora HCl 5 M aquoso, saturou-se com NaCl e extraiu-se 3 vezes com THF. Lavaram-se os extractos de THF combinados, 2 vezes, com uma solução aquosa, saturada, de NaCl e secou-se sobre Na2S04. A evaporação in vacuo originou o composto do título. EM (m/e) : 24 9,0 (M+NH4+, 100 %) , 231,9 (M+H+, 63 %) (c) Éster metílico do ácido 2-hirdroxi-5-metilsulfamoil-benzóico A 77 mmole do ácido 2-hidroxi-5-metilsulfamoil-benzóiço, no seio de 300 mL de THF, adicionou-se 85 mmole de CDI e aqueceu-se a mistura a 70 °C, durante 1 hora. Adicionou-se então 770 mmole de metanol e aqueceu-se a mistura a 70 °C, durante 16 horas. Arrefeceu-se então a mistura para a temperatura ambiente e concentrou-se in . vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de etilo/heptano/diclorometano a 45:45:10), para se obter o composto do título. EM (m/e): 244,1 ([M-H]&quot;, 100 %) (d) Éster metílico do ácido 2-isobutoxi-5-metilsulfamoil-benzóico A 2,9 mmole do éster metílico do ácido 2-hidroxi-5-metilsulfamoil-benzóico, 3,1 mmole de 2-metil-l-propanol e 3,3 mmole de trifenilfosfina, no seio de 10 mL de THF, adicionou-se 3,1 mmole de azodicarboxilato de di-terc-butilo e. agitou-se a mistura à TA, durante 2 horas. 149Preparation of 2-isobutoxy-5-methylsulfamoylbenzoic acid (a) 5-Chlorosulfonyl-2-hydroxy-benzoic acid To 3.26 mol of chlorosulfonic acid at 0 ° C was added 652 mmol of salicylic acid in small portions and the mixture was allowed to stir at RT for 1 hour, then at 50 ° C for 1 hour and finally at 70 ° C for 1 hour. The mixture was then added dropwise to 1000 mL of ice water, with stirring, and stirring was continued for an additional 30 minutes. The resulting white crystals were collected by filtration, washed three times with water and then dried in vacuo at 45øC for 16 hours to give the title compound. MS (m / e): 236.8 (({{37C1} MH]; 33%), .235.0 ([{37Cl} MH], 100%) (b) 2-Hydroxy-5-methylsulfamoylbenzoic acid To 63 mmole of 5-chlorosulfonyl-2-hydroxy-benzoic acid in dichloromethane (120 mL) at RT was added dropwise 317 mmol of methylamine (ethanol solution 8 M) and the mixture was allowed to stir at RT for 1 hour. The mixture was then concentrated in vacuo. The residue was suspended in 1M aqueous NaOH solution and extracted 2x with ether. The aqueous phase was acidified with aqueous 5 M HCl, saturated with NaCl and extracted 3 times with THF. The combined THF extracts were washed 2 times with saturated aqueous NaCl solution and dried over Na 2 SO 4. Evaporation in vacuo gave the title compound. MS (m / e): 249.0 (M + NH4 +, 100%), 231.9 (M + H +, 63%) (c) 2-Hydroxy-5-methylsulfamoyl- benzoic acid methyl ester To 77 mmol of 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 mL of THF was added 85 mmol of CDI and the mixture was heated at 70 ° C for 1 hour. 770 mmol of methanol was then added and the mixture was heated at 70 ° C for 16 hours. The mixture was then cooled to room temperature and concentrated in vacuo. vacuum. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane / dichloromethane 45:45:10) to give the title compound. (D) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester To 2.9 mmole of 2-hydroxy- 5-methylsulfamoylbenzoic acid, 3.1 mmol of 2-methyl-1-propanol and 3.3 mmol triphenylphosphine in 10 mL of THF was added 3.1 mmol of di-tert-butyl azodicarboxylate and . the mixture was stirred at RT for 2 hours. 149

Concentrou-se então a mistura in vacuo. Fez-se a cromato-grafia do resíduo . em gel de sílica (eluente: acetato de etilo/heptano a 2:3), para se obter o composto do título. EM (m/e): 300,2 ([M-H]-, 100 %) (e) Ácido 2-lsobutoxi-5-m.etilsulfamoil-benzóico A 3,3 mmole. do éster metílico do ácido 2-isobutoxi-5-metilsulfamoil-benzóico, no seio de 10 mL de THF, adicionou-se 20 mmole de uma mistura aquosa de NaOH 2 M e aqueceu-se a mistura a 50 °C, durante 2 horas. Depois arrefeceu-se a mistura para a TA e extraiu-se 2 vezes com éter. Acidificou-se a fase aquosa com ácido cítrico aquoso a 10 % e extraiii-se 3 vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas sobre Na2S(V. Ã evaporação in vacuo seguida de trituração no seio de éter, originou o composto do título.' EM (m/e): 286,2 ([M-H.]-, 100 %)The mixture was then concentrated in vacuo. The residue was chromatographed. on silica gel (eluent: ethyl acetate / heptane 2: 3) to give the title compound. MS (m / e): 300.2 ([M-H] -, 100%) (e) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid To 3.3 mmole. of 2-isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester in 10 mL of THF was added 20 mmol of a 2M aqueous NaOH mixture and the mixture was heated at 50 ° C for 2 hours . The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aqueous citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried over Na 2 S (evaporation in vacuo followed by trituration in ether gave the title compound. MS (m / e): 286.2 ([MH +] -, 100% )

Em analogia com os exemplos 6.1 (d) e (e), prepararam-se os compostos 6.2 a 6.10 do quadro que se segue, a partir do éster metílico do ácido 2-hidroxi-5-metilsulfamoil-benzóico e do álcool apropriado, seguido de hidrólise com hidróxido de· sódio aquoso:In analogy to examples 6.1 (d) and (e), compounds 6.2 to 6.10 of the table below were prepared from 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and the appropriate alcohol, followed of hydrolysis with aqueous sodium hydroxide:

Exemp. Ne. Nome Sistemático Álcool EM (m/e&gt; 6.2 ácido 2-(2, 2-dimetil-propoxi)-5-itietano-sulfonil-benzóico 2,2-dimetil-l-propanol 300,2 (M-H) 6.3 ácido 2-isopropoxi-5-metil-sulfamoil-benzóico 2-propanol 272,2 (M-H) &quot; 6.4 ácido 2-ciclopentiloxi-5-metil-sulfamoil-benzóico ciclopentanol 29S, 2 (M-H) 6.5 ácido 2-ciclobutoxi-5-metil-sulfamoil-benzóico ciclobutanol 284,1 (M-H) ' 6.6 ácido 2-ciclopropilmetoxi-5-metil-sulfamoil-benzóico ciclopropil-metanol 284,1 (M-H) 6.7 ácido 2-ciclobutilmetoxi-5-metil- ciclobutil-metanol 298,2 150 sulfamoil-benzóico (M-H) 6.8 ácido 5-metil-sulfamoil-2-(tetra- tetra-hidr.o-2H-piran-4- 314,1 hidro-piran-4-iloxi)-benzóico ol (M-H) 6.9 ácido 2-(2-metoxi-etoxi)-5-metilsulfamoil-benzóico 2-mstoxi-etanol 288,1 (M-H) 6.10 ácido 5-metil-sulfamoil-2-(3,3, 3-trifluoro-propoxi)-benzóico 3,3,3-trifluoro-l-propanol 326,2 (M-H)Exemp. Huh. 6.2.2 2- (2,2-dimethyl-propoxy) -5-methylethanesulfonyl-benzoic acid 2,2-dimethyl-1-propanol 300.2 (MH) 6.3 2-isopropoxy acid -5-methylsulfamoyl-benzoic acid 2-propanol 272.2 (MH) &quot; 6.4 2-cyclopentyloxy-5-methylsulfamoylbenzoic acid cyclopentanol 29S, 2 (MH) 6.5 2-Cyclobutoxy-5-methylsulphamoyl cyclopropylmethanol 284.1 (MH) 6.7 2-cyclobutylmethoxy-5-methylcyclobutylmethanol 298.2 150 sulfamoyl acid 284.1 (MH) 6.6 2-cyclopropylmethoxy-5-methylsulphamoyl- benzoic acid (MH) 6.8 5-methylsulfamoyl-2- (tetrahydro-2H-pyran-4-yl) -hydroxy-4-yloxy) -benzoic acid (MH) 2-methoxy-ethoxy) -5-methylsulfamoyl-benzoic acid 2-methoxy-ethanol 288.1 (MH) 6.10 5-methylsulphamoyl-2- (3,3,3-trifluoro-propoxy) 3,3-trifluoro-1-propanol 326.2 (MH)

Exemplo 6.11Example 6.11

Preparação do ácido 5-metilsulfamoil-2“(2,2,2-trifluoro-etoxi)-benzóico (a) Éster metilico do ácido 5-metilsulfanioil-2- (2,2,2-trifluoro-etoxi) -benzóico A 3,3 mmole do éster metilico do ácido 2-hidroxi-5-metilsulfamoil-benzóico e 3,3 mmole de carbonato de potássio, no seio de 50 mL de acetona, adicionou-se, gota a gota, 4,9 mmole sulfonato de 2,2,2-trifluoro-etil-trifluo-rometano e aqueceu-se a mistura a 60 °C, durante 16 horas. Concentrou-se então a mistura in vacuo. Fez-se uma .suspensão do resíduo no seio. de diclórometano e filtrou-se. Concentrou-se o filtrado in vacuo e fez-se a cromatografia do resíduo em gel de silica (eluente: acetato de eti-lo/heptano a 3:7), para se obter o composto do título. EM (m/e): 328,0 (K+H+, 100 %) (b) Ácido .5-metilsulfamoil-2-(2,2,2-trifluoro-etoxi)-ben-zóico A 2,3 mmole do éster, metilico do ácido 5-metilsul-famoil-2-(2,2,2-trifluoro-etoxi)-benzóico, no seio de 10 mL de THF, adicionou-se 20 mmole de NaOH 2 M aquoso e aqueceu-se a mistura a 50 °C, durante 2 horas. Arrefeceu-se então a mistura para a TA e extraiu-se 2 vezes com éter. 151Preparation of 5-methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (a) 5-Methylsulfanyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid methyl ester , 3 mmol of 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol of potassium carbonate in 50 mL of acetone was added dropwise, 2.9 mmol , 2,2-trifluoro-ethyl-trifluoromethane and the mixture was heated at 60 ° C for 16 hours. The mixture was then concentrated in vacuo. Suspension of the residue in breast. of dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluent: ethyl acetate / heptane 3: 7) to give the title compound. (B) 5-Methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid To 2.3 mmole of 5-methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid methyl ester in 10 mL of THF was added 20 mmol of aqueous 2 M NaOH, and mixture at 50 ° C for 2 hours. The mixture was then cooled to RT and extracted twice with ether. 151

Acidificou-se. a fase aquosa com ácido cítrico aquoso a 10 % e extraiu-se 3 vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas com Na2S04. A evaporação in vacuo seguida da trituração no seio de éter, originou o composto do titulo. EM (m/e): 312,0 ([M-H]&quot;, 100 %)Acidified. the aqueous phase with 10% aqueous citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m / e): 312.0 ([M-H] &quot;, 100%)

Exemplo 6.19Example 6.19

Preparação do ácido rac-5-metilsulfamoil-2-(2,2,2-trifluo-ro-l-metil-etoxi)-benzóieo (a) Éster metilico, do ácido rac-5-metilsulfamoil-2- (2,2,2-? trifluoro-l-metil-etoxi)-benzóieo A 4,1 mmole do éster metilico do ácido 2-hidroxi-5-metilsulfamoil-benzóiço e 4,1 mmole de carbonato de potássio, nó seio de 5 mL de DMF, adicionou-se, gota a gota, 6,1 mmole do éster 2,2,2-trifluoro-l-metil-etílico do ácido trifluoro-metano-sulfónico e aqueceu-se . a mistura a 9.0 °C, durante 16 horas. Arrefeçeu-se então a mistura para a TA, verteu-se em água e extraiu-se 3 vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas com Na2SC&gt;4. A evaporação in vacuo seguida de cromatografia em gel de sílica (eluente: diclorometano), originou o composto do título. EM (m/e) : 359,2 (M+NH4+, 80 %) , 342, 0 (M+H+, 100 %) (b) Ácido rac-5-metilsulfamoil-2-(2,2,2-trifluoro-l-metil-etoxi) -benzóieo A 1,6 mmole do éster metilico do ácido 5-metilsul-famoil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóieo, no seio de 10 mL de THF, adicionou-se 20 mmole de NaOH aquoso 2 M e aqueceu-se a mistura a 50 °C, durante 2 horas. Arrefeceu-se então a mistura para a TA e extraiu-sê 2 vezes com éter. 152Preparation of rac-5-methylsulfamoyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (a) Rac-5-methylsulfamoyl-2- , 2-trifluoro-1-methyl-ethoxy) -benzoic acid methyl ester To 4.1 mmole of 2-hydroxy-5-methylsulfamoyl-benzylic acid methyl ester and 4.1 mmole of potassium carbonate in 5 mL DMF , 6.1 mmol of trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester was added dropwise and heated. the mixture at 9.0 ° C for 16 hours. The mixture was then cooled to RT, poured into water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2 SO4 &gt; 4. Evaporation in vacuo followed by silica gel chromatography (eluent: dichloromethane) provided the title compound. MS (m / e): 359.2 (M + NH4 +, 80%), 342.0 (M + H +, 100%) (b) rac-5-methylsulfamoyl-2- (2,2,2- methyl-ethoxy) -benzoic acid methyl ester To 1.6 mmole of 5-methylsulfamoyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid methyl ester in 10 mL of THF, 20 mmol of 2M aqueous NaOH was added and the mixture was heated at 50 ° C for 2 hours. The mixture was then cooled to RT and extracted 2x with ether. 152

Acidificou-se a fase aquosa com ácido cítrico aquoso a 10 % e extraiu-se 2 vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas com Na2S04. A evaporação ín vácuo seguida da trituração com éter e hexano originou o composto do título. EM (m/e): 326,2 ([M-H]100 %)The aqueous phase was acidified with 10% aqueous citric acid and extracted 2 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration with ether and hexane provided the title compound. MS (m / e): 326.2 ([M-H] 100%)

Exemplo 6.14Example 6.14

Preparação do ácido S-ciclopropano-sulfonil-^-isopropoxi-benzóico (a) Ácido 2-hidroxi-5-sulfino-benzóico A 317 mmole de sulfito de sódio, no seio de 200 mL de água, à TA, adicionou-se, gota a gota, durante 30 minutos, uma solução de 42,3 mmole do ácido 5-cloro-sulfonil-2-hidroxi-benzóico, no seio de 80 mL de dioxano e agitou-se, continuadamente, durante mais 30 minutos. Depois adicionou-se, gota a gota,' NaOH aquoso 5 M até a mistura reaccional ter um pH de 14 e depois deixou-se a mistura em agitação à. TA, durante mais 2 horas. Arrefeceu-se então a mistura para 0 °C e adicionou-se H2S04 concentrado até a mistura reaccional ter um pH de 1. Adicionou-se acetato de etilo e separaram-se as fases. Secou-se a fase orgânica com Na2S04. A evaporação ín vacuo originou, o composto do título. EM (m/e): 201,0 ([M-H]&quot;, 100 %} . (b) Ácido 5-(3-cloro-propano-l-sulfonil)-2-hidroxi-ben- zóico A 16,7 mmole do ácido 2-hidroxi-5-sulfino-benzóico e 41,7 mmole de trietilamina, no seio de 40 mL de DMF, adicionou-se 18,3 mmole de l-cloro-3-iodopropano e aqueceu-se a mistura a 40 °C, durante 1 hora. Arrefeceu-se então a 153 mistura para a temperatura ambiente e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: gradiente de diclorometano/metanol/ácido acético), para se obter o composto do título. EM (m/e): 279,1 ( [{37C1}M-H]“, 33 %), 277,0 { [ {35C1}M-H]&quot;, 100 %) (c) Ácido 5&quot;ciclopropano-sulfoníl&quot;2-hidroxi-benzóico A 8,0 irunole do ácido 5- (3-cloro-propano-l-sulfonil) -2-hidroxi-benzóico, no seio de 30 mL de THF, a -78 °C, adicionou-se, gota a gota, durante 30 minutos, 23,9 irunole de uma solução de bis(trimetilsiiil)amida de potássio 0,9 M, no seio de tolueno. Deixou-se a mistura reaccional aquecer até à TA e agitou-se, continuadamente, durante mais 30 minutos, à TA. Diluiu-se então a mistura com THF/acetato de etilo (1:1) e lavou-se, sequencialmente, com HC1 aquoso 1 M e uma solução de NaCl aquosa, saturada, secou-se com Na2S04 e concentrou-se in vacuo. Triturou-se o resíduo no seio de. éter/pentano, para se obter o. composto do título. EM (m/e): 241,2 ([M-H]~, 100 %) (d) Éster metllico do ácido, 5-ciclopropano-sulfonil-2-hidroxi-benzóico A 7,2 mmole do ácido 5-ciclopropano-sulfoníl-2-hidroxi-benzóico, no seio de 20 mL de dicloroetano contendo algumas gotas de DMF, adicionou-se, gota a gota, 8,7- mmole de cloreto: de .oxalilo. Depois de se agitar durante 90 minutos, â TA, arrefeceu-se a mistura reaccional para 0 °C e depois adicionou-se 144 mmole de metanol seguido de 72 mmole de piridina e agitou-se, continuadamente,. à TA, durante' 1 hora. Lavou-se então a mistura com HC1 aquoso 1 M, secou-se com NajSC^, e concentrou-se in vacuo. Fez-se a cromatografia do. resíduo em gel de sílica (eluente: 154 gradiente de acetato de etilo/heptano), para se obter o composto do titulo. EM (m/e): 255,2 {[M-H]-, 100 %) (e) Ácido 5-ciclopropano-sulfonil-2-isopropoxi-benzóico A 0,6 mmole do éster metilico do ácido 5-ciclopropano-sulfonil-2-hidroxi-benzóÍco, 3,7 mmole de 2-propanol e 0,9 mmole de difenil-2-piridilfosfina, no seio de 8 mL THF, adicionou-se 0,9 mmole de azodicarboxilato de di-terc-butilo e agitou-se a mistura à TA, durante 3 horas. Adicionou-se então 4 mmole de uma solução dé NaOH aquosa 5 M e aqueceu-se a mistura a 60 °C, durante 1 hora.Preparation of S-cyclopropane-sulfonyl-Î ± -isopropoxy-benzoic acid (a) 2-Hydroxy-5-sulfinobenzoic acid To 317 mmol of sodium sulfite in 200 mL of water at RT was added, A solution of 42.3 mmol of 5-chlorosulfonyl-2-hydroxy-benzoic acid in 80 mL of dioxane was added dropwise over 30 minutes and the mixture was stirred for a further 30 minutes. Thereafter, 5 M aqueous NaOH was added dropwise until the reaction mixture had a pH of 14 and then the mixture was allowed to stir. TA for an additional 2 hours. The mixture was then cooled to 0 ° C and concentrated H2 SO4 was added until the reaction mixture had a pH of 1. Ethyl acetate was added and the phases were separated. The organic layer was dried with Na2SO4. Evaporation in vacuo gave the title compound. (B) 5- (3-Chloro-propane-1-sulfonyl) -2-hydroxy-benzoic acid A 16.7 (m / e): 201.0 ([MH] of 2-hydroxy-5-sulfinobenzoic acid and 41.7 mmol of triethylamine in 40 mL of DMF was added 18.3 mmol of 1-chloro-3-iodopropane and the mixture was heated at The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / methanol / acetic acid gradient), to give the title compound: MS (m / e): 279.1 ([(37C) MH], 33%), 277.0 ([(35C1MH) 5- (3-Chloro-propane-1-sulfonyl) -2-hydroxy-benzoic acid in 8.0 mL of THF at -78 ° C At 0 ° C, 23.9 mmol of a solution of 0.9 M potassium bis (trimethylsilyl) amide in toluene was added dropwise over 30 minutes. The reaction mixture was allowed to warm to RT and stirred continuously for a further 30 minutes at RT. The mixture was then diluted with THF / ethyl acetate (1: 1) and washed sequentially with 1M aqueous HCl and a saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with ethyl acetate. ether / pentane, to give compound of the title. (M / e): 241.2 ([MH] +, 100%) (d) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester To 7.2 mmole of 5-cyclopropanesulfonyl -2-hydroxy-benzoic acid in 20 mL of dichloroethane containing a few drops of DMF was added dropwise 8.7 mmol of oxalyl chloride. After stirring for 90 minutes at RT, the reaction mixture was cooled to 0 ° C and then 144 mmol of methanol followed by 72 mmol of pyridine was added and the mixture was stirred continuously. at RT for 1 hour. The mixture was then washed with 1 M aqueous HCl, dried over Na2 SO4, and concentrated in vacuo. Chromatography of. residue (silica gel eluent: ethyl acetate / heptane gradient) to give the title compound. 5-Cyclopropanesulfonyl-2-isopropoxy-benzoic acid To 0.6 mmol of 5-cyclopropanesulphonyl-4-methoxy- 2-hydroxy-benzoic acid, 3.7 mmol of 2-propanol and 0.9 mmol diphenyl-2-pyridylphosphine in 8 mL THF was added 0.9 mmol di-tert-butyl azodicarboxylate and stirred The mixture was stirred at RT for 3 hours. 4 mmol of a 5M aqueous NaOH solution was then added and the mixture was heated at 60 ° C for 1 hour.

Concentrou-se então a mistura in vacuo. Fez-se uma nova suspensão do residuo nó seio de acetato de etilo e lavou-se 2 vezes com uma solução de NaOH aquosa 1 M. Acidificaram-se então as fases aquosas combinadas para pH de 1 por adição de HC1 aquoso a 25 %' e extraiu-se 3 vezes com acetato de etilo. Secaram-se então os extractos orgânicos combinados com Na2S04 e concentrou-se ; in vacuo, para se obter o composto do titulo. EM , (m/e) : 282,9 ([Μ—H]“, 100 %)The mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and washed 2 times with 1M aqueous NaOH solution. The combined aqueous phases were then acidified to pH 1 by the addition of 25% aqueous HCl, and extracted 3 times with ethyl acetate. The combined organic extracts were then dried with Na2SO4 and concentrated; in vacuo to give the title compound. MS, (m / e): 282.9 ([Μ-H], 100%)

Em analogia com o exemplo 6.14 (e) , prepararam-se os compostos 6.15 a 6.18 do quadro que se segue, a partir do éster metilico do ácido 5-ciclopropano-sulfonil-2-hidroxi-benzóico e do álcool apropriado, seguido de hidrólise' com hidróxido de sódio aquoso:In analogy to example 6.14 (e), compounds 6.15 to 6.18 of the following table were prepared from 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester and the appropriate alcohol, followed by hydrolysis with aqueous sodium hydroxide:

Exemp. N°. Nome Sistemático Álcool EM (m/e) 6.15 ácido 5-ciclopropano-sulfonil-2-. isobutoxi-benzóico 2-metil-l-propanol 297,1 (M-H) 6.16 ácido 2-ciclopentiloxi-5-ciclopropano-sulfonil-benzóico ciclopentanol 309,1 (M-H) 6.17 ácido 5-ciclopropano-sulfonil-2-ciclopropilmetoxi-benzóico ciclopropil-metanol 295,2 (M-H) 6.18 ácido 2-ciclobutoxi-5^ciclopropano-sulfonil-benzóico ciclobutanol 295,2 (M-H) 155Exemp. No. Systematic Name Alcohol MS (m / e) 6.15 5-Cyclopropanesulfonyl-2- 1-propanol 297.1 (MH) 6.16 2-cyclopentyloxy-5-cyclopropanesulfonylbenzoic acid cyclopentanol 309.1 (MH) 6.17 5-cyclopropanesulfonyl-2-cyclopropylmethoxy-benzoic acid cyclopropyl -methanol 295.2 (MH) 6.18 2-cyclobutoxy-5-cyclopropanesulfonylbenzoic acid cyclobutanol 295.2 (MH) 155

Exemplo 6.12Example 6.12

Preparação de 1-(4-etano-sulfonil-2-fluoro-fenil)-piperazi-na (a) Ácido 3, 4-dlfluoro-be.nzeno-sulflnico A 2,47 mole de sulfito de sódio, no seio de 1.120 mL de água, à TA, adicionou-se, gota a gota, durante 20 minutos, uma solução de 329 mmole de cloreto de 3,4-dífluoro-benzeno-sulfonilo, no seio de 560 mL de dioxano e agi.tou-se, continuadamente, durante mais 30 minutos. Adicionou-se então, gota a gota, NaOH aquoso 1 M até a mistura reaccional ter um pH de 14 e depois deixou-se a mistura em agitação à TA, durante mais 16 horas. Arrefeceu-se então a mistura para 0 °C e adicionou-se H2S04 concentrado até a mistura reaccional ter um pH de 1. Extraiu-se a mistura 3 yezes com acetato de etilo e lavaram-se as fases orgânicas combinadas com uma solução de NaCl aquoso, saturado e depois secou-se com Na2S04. A evaporação in vacuo, originou o composto do titulo. EM (m/e): 177,1 {[M-H]~ 100 %) (b) 4-Etano-sulfonil-l,2-difluoro-benzeno A '3,0 mmole do ácido 3,4-difluoro-benzeno-sulfinico e 3,0 mmole de trietilamina, no seio de 10 mL DMF, adicionou-se 7,5 mmole de iodoetano e aqueceu-se a mistura a 90 °C, durante 9 horas. Verteu-se então a mistura reaccional em água e extraiu-se 3 vezes com acetato de etilo. Lavaram-se então as fases orgânicas combinadas com uma solução de NaCl aquoso, saturado, secou-se sobre Na2S04 e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de etilo/heptano a 1:7), para. se obter o composto do título. EM (m/e): 206, 9 (M+H+, 100 %) 156 (c) 1-(4-Etano-sulfonil-2-fluoro-fenil)-piperazina A 2,0 mxnole de 4-etano-sulfonil-l,2-difluoro-benzeno, no seio de 5 mL de N,N-dimetilacetamida, adicionou-se 5,6 mmole de piperazina e aqueceu-se a mistura a 80 °C, durante 45 minutos. Concentrou-se então a mistura in vacuo, para se obter o composto do titulo. EM (m/e): 273,0 (M+H+, 100 %)Preparation of 1- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (a) 3,4-Difluorobenzenesulphonic acid To 2.47 mol of sodium sulfite in 1120 ml of water at RT was added dropwise over 20 minutes a solution of 329 mmol of 3,4-dichloro-benzenesulfonyl chloride in 560 mL of dioxane and stirred , continuously for an additional 30 minutes. 1 M aqueous NaOH was then added dropwise until the reaction mixture had a pH of 14 and then the mixture was allowed to stir at RT for an additional 16 hours. The mixture was then cooled to 0 ° C and concentrated H 2 SO 4 was added until the reaction mixture had a pH of 1. The mixture was extracted 3 times with ethyl acetate and the combined organic phases were washed with NaCl aqueous, saturated and then dried with Na2SO4. Evaporation in vacuo gave the title compound. (B) 4-Ethanesulfonyl-1,2-difluoro-benzene To 3.0 mmole of 3,4-difluoro-benzene- sulfinic acid and 3.0 mmol of triethylamine in 10 mL DMF was added 7.5 mmol of iodoethane and the mixture was heated at 90 ° C for 9 hours. The reaction mixture was then poured into water and extracted 3 times with ethyl acetate. The combined organic phases were then washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane 1: 7) to give the title compound as a white solid. to give the title compound. (C) 1- (4-Ethanesulfonyl-2-fluoro-phenyl) -piperazine To 2.0 mmole of 4-ethanesulfonyl -1,2-difluoro-benzene in 5 mL of N, N-dimethylacetamide was added 5.6 mmol of piperazine and the mixture was heated at 80 ° C for 45 minutes. The mixture was then concentrated in vacuo to give the title compound. MS (m / e): 273.0 (M + H +, 100%)

Em analogia com os exemplos 6.12 (b) e (c) , prepararam-se os compostos 6.13, e 6.21 a 6.23 do quadro que se segue, a partir do ácido 3-, 4-difluoro-benzeno-sulfínico e dos halogenetos de alquilo indicados, seguido da reacção com piperazina:In analogy to examples 6.12 (b) and (c), compounds 6.13 and 6.21 to 6.23 of the following table were prepared from 3-, 4-difluoro-benzenesulfonic acid and the alkyl halides indicated, followed by reaction with piperazine:

Exemp. N°. Home Sistemático Álcool EM &lt;m/e) 6.13 1-[4-(butano-l-sulfonil)-2- . fluoro-fenil]-piperazina iodobutano 301,1 6.21 1- (2-fluoro-4-(propane-2-. sulfonil)-fenil]-piperazina 2-iodopropano 287, 0 6.22 1- (4-ciclopropilmetano-sulfonil- 2- fluoro-fenil)-piperazina bromo-metil-ciclo-propano e Nal 299,2 6.23 1-[2-fluoro-4-(2-metoxi-etano-sulfonil)-fenil]-piperazina l-iodo-2-metoxi-etano 303, 1Exemp. No. Home Systematic Alcohol MS (m / e) 6.13 1- [4- (butane-1-sulfonyl) -2-. fluoro-phenyl] -piperazine iodobutane 301.1 6.21 1- (2-fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine 2-iodopropane 287.0 6.22 1- (4-cyclopropylmethanesulfonyl-2 2-fluoro-phenyl) -piperazine bromo-methyl-cyclopropane and Nal 299.2 6.23 1- [2-fluoro-4- (2-methoxy-ethanesulfonyl) -phenyl] -piperazine 1-iodo-2-methoxy -ethane 303.1

Exemplo 6.20Example 6.20

Preparação de 1-(4-ciclopropano-sulfonil-2-£luoro-£enil)-piperazina (a) 4- (3-Cloro-propano-l-sulfonil) -1,2-difluoro-benzeno. A 28,3 mmole do ácido 3,4-difluoro-benzeno-sulfínico.e 36,8 mmole de trietilamina, no seio de 100 mL de DMF, adicionou-se 70,7 mmole de l-cloro-3-iodopropano e agitou-se a mistura à TA, durante 1 hora. Depois verteu-se a mistura reaccional em água e extraiu-se 3 vezes com acetato 157 de etilo. Lavaram-se então as fases orgânicas combinadasPreparation of 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (a) 4- (3-Chloro-propane-1-sulfonyl) -1,2-difluoro-benzene. To 28.3 mmol of 3,4-difluoro-benzenesulfinic acid and 36.8 mmol of triethylamine in 100 mL of DMF was added 70.7 mmol of 1-chloro-3-iodopropane and stirred The mixture was stirred at RT for 1 hour. The reaction mixture was then poured into water and extracted 3 times with ethyl acetate. The combined organic phases were then washed

com uma solução de NaCl aquosa saturada, secou-se sobre Na2S04 e concentrou-se in vacuo. Fez-se a cromatografia do residuo em gel de sílica . (eluente: gradiente de acetato de etilo/heptano), para se obter o composto do título. EM (m/e): 257,2 ({37C1}M+H% 33 %) , 255,1 ({35C1}M+H+, 100 %) (b) 4-Ciclopropano-sulfonil-1, 2-dif luoro-benzeno A 11,8 mmole de 4-(3-cloro-propano-l-sulfonil)-1,2-difluoro-benzeno, no seio de 400 mL de THF, a -78 °C, adicionou-se, gota a gota, durante 30 minutos, 14,2 mmole de uma solução de bis(trimetilsilil)amida de potássio 0,9 M, no seio de THF. Deixou-se a mistura reaccional aquecer até à TA e agitou-se, continuadamente, durante mais 30 minutos, à TA. Depois parou-se a reacção por adição de' HC1 aquoso 1 M e extraiu-se três vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas com Na2SC&gt;4 e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de. etilo/heptano a 1:5), para se obter o composto do título'. EM (m/e): 219,2 (M+H+, 100 %) (c) 1-(4-Ciclopropano-sulfonil-2-fluoro-fenil)-piperazina A 0,2 mmole de 4-ciclopropano-sulfonil-l,2-difluoro-benzeno, no seio de 5 mL de Ν,Ν-dimetilacetamida, adicionou-se 0,5 mmole de: piperazina e aqueceu-se a mistura a 80 °C, durante 90 minutos. Concentrou-se então a mistura in vacuor para se obter o composto do título. EM (m/e): 285,0 (M+H\ 100 %)with a saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel. (eluent: ethyl acetate / heptane gradient) to give the title compound. MS (m / e): 257.2 ({37C1} M + H% 33%), 255.1 ({35C1} M + H +, 100%) (b) 4-Cyclopropanesulfonyl- benzene To 11.8 mmol of 4- (3-chloro-propane-1-sulfonyl) -1,2-difluoro-benzene in 400 mL of THF at -78 ° C was added dropwise was added dropwise over 30 minutes 14.2 mmol of a solution of 0.9 M potassium bis (trimethylsilyl) amide in THF. The reaction mixture was allowed to warm to RT and stirred continuously for a further 30 minutes at RT. The reaction was then quenched by addition of 1 M aqueous HCl and extracted three times with ethyl acetate. The combined organic phases were dried with Na2 SO4 &lt; 4 &gt; and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: 1: 5 ethyl acetate / heptane) to give the title compound. (C) 1- (4-Cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine To 0.2 mmole of 4-cyclopropanesulfonyl- 1,2-difluoro-benzene in 5 mL of N, N-dimethylacetamide was added 0.5 mmol of: piperazine and the mixture was heated at 80 ° C for 90 minutes. The mixture was then concentrated in vacuo to give the title compound. MS (m / e): 285.0 (M + H +, 100%)

Exemplo 6.24 158Example 6.24

Preparação do cloridrato de 1-(4-ciclábutano-sixlfonil-2-fluoro-fenil)-piperazina (a) 4-Ciclobutano-sulfonil-l,2-difluoro-benzeno A 5,6 mmole do ácido 3,4-difluoro-benzeno-sulfínico e 6,2 mmole de trietilamina, no seio de 10 mL de' DMF, adicionou-se 8,4 mmole de bromociclobutano e 0,2 mmole de iodeto de sódio e aqueceu-se a mistura a 100 °C, durante 48 horas. Depois verteu-se a mistura reaccional em água e extraiu-se 3 vezes com acetato de etilo. Lavaram-se então as fases orgânicas· combinadas com uma solução NaCl aquosa, saturada, secou-se sobre Na2S04, e concentrou-se in vacuo. Fez-se. a cr.omat.ografia do resíduo em gel de sílica (eluente: gradiente de acetato de etilo/heptano), para se obter o composto do título. EM (m/e): 233,1 (M+H+, 100 %) (b) Cloridrato de 1-^-ciclobutano-sulfonil-^-fluoro-fe- nil)-piperazina A 2,8 mmole de 4-ciclobutano-sulfonil-l,2-difluoro-benzeno, no seio de 20 mL de Ν,Ν-dimetilacetamida, adicionou-se 8,3 mmole de piperazina e aqueceu-se a mistura a 80 °C, durante 45 minutos. Concentrou-se então a mistura in vacuo e fez-se a cromatografia do resíduo em gel de sílica {eluente: gradiente de acetato de etilo/metanol). Combinaram-se as fracções contendo o produto e concentrou-se in vacuo. Fez-se uma nova suspensão do resíduo em 100 mL de dioxano e 6,0 mmole de HC1 (sob a forma de uma solução de dioxano 4 M), que se adicionou. Depois de se agitar durante 10' minutos,recolheram-se os cristais brancos resultantes por filtração,, lavaram-se 2 vezes com éter, para se obter o composto do título. EM (m/e): 299,1 (M+H+, 100 %} 159Preparation of 1- (4-Cyclobutane-six-sulfonyl-2-fluoro-phenyl) -piperazine hydrochloride (a) 4-Cyclobutanesulfonyl-1,2-difluorobenzene To 5.6 mmol of 3,4- benzenesulphonic acid and 6.2 mmol of triethylamine in 10 mL of DMF was added 8.4 mmol of bromocyclobutane and 0.2 mmol of sodium iodide and the mixture was heated at 100 ° C for 48 hours. The reaction mixture was then poured into water and extracted 3 times with ethyl acetate. The combined organic phases were then washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated in vacuo. It was done. chromatography of the residue on silica gel (eluent: ethyl acetate / heptane gradient) to give the title compound. MS (m / e): 233.1 (M + H +, 100%) To 2.8 mmole of 4-cyclobutane 2-difluoro-benzene in 20 mL of Î ±, β-dimethylacetamide was added 8.3 mmol of piperazine and the mixture was heated at 80 ° C for 45 minutes. The mixture was then concentrated in vacuo and the residue was chromatographed on silica gel (eluent: ethyl acetate / methanol gradient). The fractions containing the product were combined and concentrated in vacuo. The residue was resuspended in 100 mL of dioxane and 6.0 mmol of HCl (as a 4 M dioxane solution), which was added. After stirring for 10 minutes, the resulting white crystals were collected by filtration, washed 2 times with ether, to give the title compound. MS (m / e): 299.1 (M + H +, 100%) 159

Em analogia com os exemplos 6.24 (a) e (b) ,- preparou-se o composto 6.25 do quadro que se segue, a partir do ácido 3,4-difluoro-benzeno-sulfinico, bromociclobutano e iodeto de sódio, seguido da reacçâo com piperazina e subsequente tratamento com HC1 no seio de dióxano:In analogy to examples 6.24 (a) and (b), compound 6.25 of the following table was prepared from 3,4-difluoro-benzenesulfinic acid, bromocyclobutane and sodium iodide, followed by reaction with piperazine and subsequent treatment with HCl in dioxane:

Exemp. Nome Sistemático Álcool EM (m/e) 6.25 cloridrato de l-(4-ciclopentano-sulfonil-2-flúoro-fenil)-piperazina Ácido difluoro-benzeno-sulfinico e bromociclopentano 313,3Exemp. Systematic Name Alcohol EM (m / e) 6.25 1- (4-cyclopentanesulfonyl-2-fluoro-phenyl) -piperazine hydrochloride Difluoro-benzenesulfonic acid and bromocyclopentane 313.3

Exemplo 6.26Example 6.26

Preparação de 1-[2-fluoro-4-(3,3,3-trifluoro-propano-l-sul-fonil) -fenil] -piperazina (a) 1,2-difluoro-4-(3,3,3-trifluoro-propilsulfanil)- benzeno A 3,4 mmole de 3,4-difluoro-tiofenol e 5,1 mmole de 1-iodo-3,3,3-trifluoropropano, no seio de 5 mL de acetona, adicionou-se 3,7. mmole de carbonato de potássio e aqueceu-se a mistura a 140 °C, durante 3 horas, sob uma radiação de microondas. Depois verteu-se a mistura reaccional em água, e extraiu-se 3 vezes com acetato de etilo. Lavaram-se então as fases orgânicas combinadas com uma solução de NaCl aquosa, saturada, secou-se sobre Na2S04 e concentrou-se in vacuo, para se obter o composto do titulo. EM (m/e) : 243,1 (M+H\ 100 %) (b) 1,2-Difluoro-4-(3,3,3-trifluoro-propano-l-sulfonil)- benzeno 160 A 3,0 mmole de 1,2-difluoro-4-(3,3,3-trifluoro-propil-sulfanil)-benzeno, no seio de 5 ml de diclorometano, adicionou-se 8,3 mmole do ácido m-cloroperbenzóico e aqueceu-se a mistura a 50 °C, durante 48 horas. Arrefeceu-se a mistura reaccional para a temperatura ambiente e diluiu-se com diclorometano e lavou-se 3 vezes com uma solução de NaHCCb aquosa, saturada. Lavou-se então a fase orgânica com uma solução de NãCl aquosa, saturada, secou-se sobre Na2S04 e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: gradiente de acetato de eti-lo/heptano), para se obter o composto do título. EM (m/e): 275,1 (M-H', 100 %) (c) ' 1-[2-Fluoro-4-(3,3,3-trifluoro-propano-l-sulfonil)- . fenil·]-piperazina A 0,5 mmole de 1,2-difluoro-4-(3,3,3-trifluoro-propa-no-l-sulfonil)-benzeno, no seio de 5 mL de N,N-dimetila-cetamida, adicionou-se 1,5 mmole de piperazina e aqueceu-se à mistura, a 80 °C, durante 90 minutos. Concentrou-se então a mistura in vacuo e fez-se a cromatografia do resíduo em gel de sílica (eluente: gradiente de metanol/diclorome-tano), para.se obter o composto do título.. EM (m/e): 341,2 (M-H+, . 100 %)Preparation of 1- [2-fluoro-4- (3,3,3-trifluoro-propane-1-sulfonyl) -phenyl] -piperazine (a) 1,2-Difluoro-4- (3,3,3 -trifluoro-propylsulfanyl) -benzene To 3.4 mmole of 3,4-difluoro-thiophenol and 5.1 mmole of 1-iodo-3,3,3-trifluoropropane in 5 ml of acetone was added 3- , 7. of potassium carbonate and the mixture was heated at 140 ° C for 3 hours under microwave irradiation. The reaction mixture was then poured into water, and extracted 3 times with ethyl acetate. The combined organic phases were then washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo to give the title compound. (B) 1,2-Difluoro-4- (3,3,3-trifluoro-propane-1-sulfonyl) -benzene 1603, (M + H +, 100% To a solution of 4-chloro-1,2,3,4-trifluoropropylsulfanylbenzene in dichloromethane (5 ml) was added 8.3 mmole of 1,2-difluoro-4- (3,3,3-trifluoropropylsulfanyl) benzene, the mixture was stirred at 50 ° C for 48 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane and washed 3 times with a saturated aqueous NaHCO3 solution. The organic phase was then washed with a saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane gradient) to give the title compound. MS (m / e): 275.1 (M-H ', 100%) (c) 1- [2-Fluoro-4- (3,3,3-trifluoro-propane-1-sulfonyl) -. phenyl] -piperazine To 0.5 mmol of 1,2-difluoro-4- (3,3,3-trifluoro-propan-1-sulfonyl) -benzene in 5 mL of N, N-dimethyl -acetamide, 1.5 mmol of piperazine was added and the mixture was heated at 80 ° C for 90 minutes. The mixture was then concentrated in vacuo and the residue was chromatographed on silica gel (eluent: methanol / dichloromethane gradient) to provide the title compound .. MS (m / e): 341 , 2 (M-H +, 100%)

Em analogia com os exemplos 6.2 6 (a) a (c) , prepararam-se os compostos 6,27 e 6.28'do quadro que se segue, a partir de 3,4-difluoro-tiofenol e do 'agente de alquilação indicado, seguido de oxidação com ácido m-cloroperbenzóico e reacção com piperazina:In analogy to examples 6.26 (a) to (c), compounds 6.27 and 6.28 of the following table were prepared from 3,4-difluoro-thiophenol and the indicated alkylating agent, followed by oxidation with m-chloroperbenzoic acid and reaction with piperazine:

Exemp. N° . Nome Sistemático Agente de alquilação EM (m/e) 6.27 1-[2-fluoro-4-(tetra-hidro-piran-4-sulfonil)-fenil]-piperazina éster tetra-hidro-piran-4-ilíco do ácido 329,1 161 tol'ueno-4-sulfónico 6.28 1-(4-ciclo-hexano-sulfonil-2-fuoro-fenil)-piperazina iodociclo-hexano 327,3Exemp. No. Systematic Name Alkylating agent EM (m / e) 6.27 1- [2-fluoro-4- (tetrahydro-pyran-4-sulfonyl) -phenyl] -piperazine-4-carboxylic acid, tetrahydro-pyran-4- , 1 161 toluene-4-sulfonic acid 6.28 1- (4-cyclohexanesulfonyl-2-fuoro-phenyl) -piperazine iodocyclohexane 327.3

Exemplo 6.29Example 6.29

Preparação do cloridrato de 1-[2,3-difluoro-4-(propano-2-sulfonil)-fenll]-piperazina (a) 1,2,3-Trifluoro-4-(propano-2-sulfonil)-benzeno A 20,4 mmole do ácido 2,3,4-trifluoro-benzeno-sulfí-nico (preparado em analogia com o exemplo 2.20 (a), a partir do cloreto de 2,3,4-trifluorobenzeno-sulfonilo) e 61,2 mmole de trietilamina, no seiô de 20 mL de DMF, adicionou-se 40,8 mmole.de 2-iodopropano e agitou-se a mistura à temperatura ambiente, durante 16 horas. Verteu-se então a mistura reaccional em água e extraiu-se 3 vezes com acetato de etilo. Lavaram-se então as fases orgânicas combinadas, duas vezes, com uma solução de' NaCl aquosa, saturada, se.cou-se sobre Na2S04 e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de etilo/heptáno a 1:4), para se obter o composto do título. EM (m/e): 239,1 (M+H+, 100 %) (b) Éster terc-butílico do àcido: 4-(2,3-difluo.ro-4-(propa-no-2-sulfonll)-fenil]-piperazino-l-carboxílico A 7,6 mmole de 1,2,3-trifluoro-4-(propano-2-sulfonil)-benzeno, no seio de 20 mL de N, N-dimetilacetamida, adícionou-se 15,9 mmole de carboxilato de terc-butil-1-piperazina e aqueceu-se a mistura a 90 °C, durante 1 hora. Arrefeceu-se.então a mistura para a temperatura ambiente e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de etilo/heptano a 1:2), 162 para se obter o composto do título. EM (m/e): 405,2 (M+H+, 100 %) (c). Cloridrato de 1-[2,3-difluoro-4-(propano-2-sulfonil)- fenil]-piperazina A 7,5 mrnole do éster terc-butilico do ácido 4-[2,3-difluoro-4-(propano-2-sulfonil)-fenil]-piperazino-1-carbo-xílico, no seio de 100 mL de dioxano, adicionou-se 30,2 .mmole' de HC1 (sob a forma de uma solução 4 M, no seio de dioxano) e aqueceu-se a mistura a 80 °C, durante . 1 hora. Deixou-se então arrefecer a mistura para a temperatura ambiente e recolheram-se os cristais brancos resultantes por filtração, lavou-se 2 vezes com éter, para sé obter o composto do título. EM (m/e): 305,2 (M+H+, 100 %)Preparation of 1- [2,3-difluoro-4- (propane-2-sulfonyl) -phenyl] piperazine hydrochloride (a) 1,2,3-Trifluoro-4- (propane-2-sulfonyl) -benzene A 20.4 mmol of 2,3,4-trifluoro-benzenesulfonic acid (prepared in analogy to example 2.20 (a), from 2,3,4-trifluorobenzenesulfonyl chloride) and 61.2 of triethylamine in 20 ml of DMF was added 40.8 mmol of 2-iodopropane and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into water and extracted 3 times with ethyl acetate. The combined organic phases were then washed twice with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane 1: 4) to give the title compound. MS (m / e): 239.1 (M + H +, 100%) (b) 4- (2,3-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester To 7.6 mmol of 1,2,3-trifluoro-4- (propane-2-sulfonyl) benzene in 20 mL of N, N-dimethylacetamide was added 15.9 mmol of tert-butyl-1-piperazine carboxylate was added and the mixture was heated at 90 DEG C. The mixture was then cooled to ambient temperature and concentrated in vacuo. Chromatography of the residue on silica gel (eluent: 1: 2 ethyl acetate / heptane), 162 to give the title compound. MS (m / e): 405.2 (M + H +, 100%) c) 1- [2,3-Difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine hydrochloride To 7.5 mmole of 4- [2,3-difluoro-4- - (propane-2-sulfonyl) -phenyl] -piperazine-1-carboxylic acid in 100 ml of dioxane was added 30.2 mmol of HCl (as a 4 M solution in and the mixture was heated at 80 ° C for 1 hour. the mixture was refluxed for ambient temperature and the resulting white crystals were collected by filtration, washed 2 times with ether to give the title compound. MS (m / e): 305.2 (M + H +, 100%)

Em analogia com os exemplos 6.29 (a) a (c), prepararam-se os compostos 6.30, 6.32 e 6.33 do quadro que se segue, a partir dos ácidos sulfínicos indicados e. dos halogenetos de alquilo, seguido da reacção com carboxilato de terc-butil-l-piperazina e a hidrólise com HC1, no seio de dioxano:In analogy to examples 6.29 (a) to (c), compounds 6.30, 6.32 and 6.33 of the table below were prepared from the indicated sulfinic acids e. of the alkyl halides followed by reaction with tert-butyl-1-piperazine carboxylate and hydrolysis with HCl in dioxane:

Exemp. . N°. Nome Sistemático Materiais Iniciais PM encont. (M+H) 6.30' cloridrato de 1- (4-etano-sulfonil-2,3-difluoro-fenil}-piperazina ácido 2,3,4-trifluoro-benzeno-sulfínico e iodoetano 291,2 6.32 cloridrato de 1-[2,5-difluoro-4- . (propano-2-sulfonil)-fenil]-piperazina ácido 2,4,5-trifluoro-benzeno-sulfinico e 2-iodopropano 305,1 6.33 cloridrato de 1-(4-etano-sulfonil~ 2,5-difluoro-fenil)-piperazina ácido 2,4,5-trifluoro-benzenò-sulfínico e iodoetano 291,1 163Exemp. . No. Systematic Name Initial Materials PM found. (M + H) 6.30 '1- (4-ethanesulfonyl-2,3-difluoro-phenyl} -piperazine hydrochloride 2,3,4-trifluoro-benzenesulfonic acid and iodoethane 291.2 6.32 1- [2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine 2,4,5-trifluoro-benzenesulfonic acid and 2-iodopropane 305.1 6.33 1- (4-ethane sulfonyl-2,5-difluoro-phenyl) -piperazine 2,4,5-trifluoro-benzenesulfonic acid and iodoethane 291.1 163

Exemplo 6.31Example 6.31

Preparação do cloridrato de 1-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazina (a) 1-(3-Cloro-propano-l-sulfonil)-2,3,4-trifluoro-benzeno A 30,6 mmole do ácido 2,3,4-trifluoro-benzeno-sulfínico (ácido preparado em analogia com o exemplo 2.20 (a) , a partir do cloreto de 2,3,4-trifluoro-benzeno- sulfonilo) e 91,8 rnmole de trietilamina, no seio de 20 mL de DMF, adicionou-se 61,2 rnmole de l-cloro-3-iodopropano e agitou-se a mistura à temperatura ambiente, durante 1 hora. Verteu-se então a mistura reaccional em água e extraiu-se 3 vezes com acetato de etilo. Lavaram-se então as fases orgânicas combinadas, duas vezes, com uma solução de NaCl aquosa, saturada, secou-se sobre Na2S04, e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: acetato de etilo/heptano a 1:4), para se obter 0. composto do título. EM (m/e): 275,2 ({37C1}M+H+, 33 %), 273,1 ({35C1}M+H+, 100 %) (b) 1-Ciclopropano-sulfonil-2,3,4-trifluoro-benzeno - A 5,9 mmole de 1-(3-cloro-propano-l-sulfonil)-2, 3,4-trifluoro-benzeno,, no seio de 200 mL de THF, a -78 °C, adicionou-se,.gota a gota, durante 30 minutos, 7,0 mmole de uma solução de bis(trimetilsilil)amida de potássio 0,9 M, no seio de THF. Deixou-se então a mistura reaccional aquecer até à TA e agitou-se, continuadamente, durante mais 30 minutos à TA. Parou-se então a reacção por adição de HC1 aquoso 1 M e extraiu-se 3 . vezes com acetato de etilo. Secaram-se as fases orgânicas combinadas sobre NaaSCq, e concentrou-se in vacuo. Fez-se a cromatografia do . resíduo em gel de sílica (eluente: acetato de, etilo/heptano a 1:4), 164 para se obter o composto do título.. EM (m/e) : .237,2 (M+H+, 100 %) (c) Éster terc-butílico do . ácido 4-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazino-l-carboxílico A 4,2 mmole de l-ciclopropano-sulfonil-2,3,4-trifluoro-benzeno, . no seio de 20 mL de K,N-dimetilacetamida, adicionou-se 8,9 mmole de; carboxilato de terc-butil-l-piperazina e aqueceu-se a mistura a 90 °C, durante 1 hora. Arrefeceu-se então a mistura para a temperatura ambiente e concentrou-se in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: gradiente de diclorometano/acetato de etilo), para se obter o composto do título. EM (m/e): 403,3 (M+H+, 100 %) (d) Cloridrato de 1-(4-ciclopropano-sulfonil-2,3-difluoro-fenil) -pipera-zina A 3,7 mmole do éster terc-butílico do ácido 4-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazino-1-carbo-xílico, no seio de 100 . mL de dioxano, adicionou-se 14,9 mmole de HC1 (sob a forma de uma solução 4 M, no seio de dioxano) e aqueceu-se a mistura a 80 °C, durante 1 hora. Arrefeceu-se então a mistura para a temperatura' ambiente e recolheram-se os cristais brancos resultantes por filtração, lavou-se duas vezes com.éter, para se obter o composto do título. EM (m/e): 303,2 (M+H+, 100 %)Preparation of 1- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazine hydrochloride (a) 1- (3-Chloro-propane-1-sulfonyl) -2,3,4-trifluoro-benzene A 30.6 mmol of 2,3,4-trifluoro-benzenesulfonic acid (acid prepared in analogy to example 2.20 (a), from 2,3,4-trifluoro-benzenesulfonyl chloride) 8 mmol of triethylamine in 20 mL of DMF was added 61.2 mmol of 1-chloro-3-iodopropane and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted 3 times with ethyl acetate. The combined organic phases were then washed twice with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane 1: 4) to give the title compound. MS (m / e): 275.2 ({37C1} M + H +, 33%), 273.1 ({35C1} M + H +, 100%) (b) 1-Cyclopropanesulfonyl-2,3,4 -trifluoro-benzene To 5.9 mmol of 1- (3-chloro-propane-1-sulfonyl) -2,3,4-trifluoro-benzene in 200 mL of THF at -78 ° C, 7.0 mmol of a solution of 0.9 M potassium bis (trimethylsilyl) amide in THF was added dropwise over 30 minutes. The reaction mixture was then allowed to warm to RT and stirred continuously for a further 30 minutes at RT. The reaction was then quenched by addition of 1 M aqueous HCl and 3. times with ethyl acetate. The combined organic phases were dried over Na2 SO4, and concentrated in vacuo. Chromatography of. (silica gel: eluent: 1: 4 ethyl acetate / heptane), to give the title compound. MS (m / e): 237.2 (M + H +, 100%) c) tert-Butyl ester of. 4- (4-Cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazine-1-carboxylic acid To 4.2 mmol of 1-cyclopropanesulfonyl-2,3,4-trifluoro-benzene. in 20 mL of N, N-dimethylacetamide was added 8.9 mmol of; carboxylate was added and the mixture was heated at 90 ° C for 1 hour. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / ethyl acetate gradient) to provide the title compound. (D) 1- (4-Cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazin hydrochloride To 3.7 mmole of the title compound was obtained as a white solid. MS (m / e): 403.3 (M + H +, 100% 4- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester in 100 ml. mL dioxane was added 14.9 mmol HCl (as a 4M solution in dioxane) and the mixture was heated at 80 ° C for 1 hour. The mixture was then cooled to ambient temperature and the resulting white crystals were collected by filtration, washed twice with ether, to give the title compound. MS (m / e): 303.2 (M + H +, 100%)

Em analogia com os exemplos 6.31 (a) a (d), preparou-se o composto 6.34 do quadro que se segue, do ácido sulfínico indicado e do halogeneto de alquilo, seguido do tratamento com bis(trimetilsilil)amida de potássio, reacção 165 com o carboxilato de terc-butil-l-piperazina e desprotecção com HC1, no seio de dioxano:In analogy to examples 6.31 (a) to (d), the following compound of the following table of sulfinic acid and alkyl halide was prepared, followed by treatment with potassium bis (trimethylsilyl) amide, reaction 165 with tert-butyl-1-piperazine carboxylate and deprotection with HCl in dioxane:

Exemp. N°. Nome Sistemático Materiais Iniciais ' . PM encont. (M+H) cloridrato de 1-(4-ciclopropano- ácido 2,4,5-trifluoro- 6.34 sulfonil-2,5-difluoro-fenil)- benzeno-sulfínico e 2- 303,1 piperazina iodopropanoExemp. No. Systematic Name Initial Materials'. PM found (M + H) 1- (4-cyclopropane-2,4,5-trifluoro-6,34-sulfonyl-2,5-difluoro-phenyl) -benzenesulfonic acid hydrochloride and 2-hydroxy-2-piperazinium iodopropane hydrochloride

Exemplo 6.35Example 6.35

Preparação de cloridrato de rac-2-metil-l-(4-trifluoro-metil-fenil)-piperazina (a) Éster terc-butllico do ácido rac-3-metil-4-(4-trifluorometil-fenil)-piperazino-l-carboxilico A l-bromo-4-trifluorometil-benzeno (1 g) , éster terc-butilico do ácido rac-3-metil-piperazino-l-carboxilico (g), no seio de tolueno (10 mL) , adicionou-se terc-butilato de sódio (0,6 g) , 2-(diciclo-hexilfosfino)bifenilo (31 mg), e tris(dibenzilideno-acetona)Pd-CHCl3 (23 mg). Agitou-se então a mistura reaccional a 80 ' °C, durante a noite. Adicionou-se então acetato de etilo à mistura reaccional. Filtraram-se os sólidos. Concentrou-se então o filtrado in vácuo e purificou-se o resíduo poi cromatografia em coluna, para se obter 0,46 g do composto do título. EM (m/e): 345,2 (M+H+, 100. %) (b) Cloridrato de rac-2-metil-l-(4-trifluorometil-fenil)-piperazina A 0,58 .mmole do éster terc-butílico do ácido rac-3-metil-4-(4-trifluorometil-fenil)-piperazino-l-carboxílico, no seio de 3 mL de dioxano, a.dicionou-se 8,7 mmole de HC1 166 (sob a. forma de uma solução 4 M, no seio de dioxano) e aqueceu-se a mistura a 90 °C, durante 3 horas. Arrefeceu-se então a mistura para 0 °C e diluiu-se com 10 mL de éter. Recolheram-se os cristais brancos resultantes por filtração, lavou-se com éter e secou-se in vácuo, para se obter o composto do titulo. EM (m/e): 245,1 (M+H+, 100 %)Preparation of rac-2-methyl-1- (4-trifluoromethyl-phenyl) -piperazine hydrochloride (a) rac-3-Methyl-4- (4-trifluoromethyl-phenyl) -piperazine- 1-carboxylic acid 1-bromo-4-trifluoromethyl-benzene (1 g), rac-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (g) in toluene (10 ml) (0.6 g), 2- (dicyclohexylphosphino) biphenyl (31 mg), and tris (dibenzylideneacetone) Pd-CHCl 3 (23 mg) were added. The reaction mixture was then stirred at 80 ° C overnight. Ethyl acetate was then added to the reaction mixture. The solids were filtered. The filtrate was then concentrated in vacuo and the residue purified by column chromatography to give 0.46 g of the title compound. (B) Rac-2-methyl-1- (4-trifluoromethyl-phenyl) -piperazine hydrochloride To 0.58 mole of the tert -butyl ester 3-methyl-4- (4-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid ethyl ester in 3 ml of dioxane was added 8.7 mmol of HCl 166 (under a). form of a 4M solution in dioxane) and the mixture was heated at 90 ° C for 3 hours. The mixture was then cooled to 0 ° C and diluted with 10 mL of ether. The resulting white crystals were collected by filtration, washed with ether and dried in vacuo to give the title compound. MS (m / e): 245.1 (M + H +, 100%)

Exemplo 6.36Example 6.36

Preparação do ácido 5-acetil-2-isopropoxi-benzóico (a) Éster metilico do ácido 5-acetil-2-isopropoxi-benzóico A 25,8 mmole de metil-5-acetil-2-hidroxibenzoato, 28,3 mmole de 2-propanol e 29,6 mmole de trifenilfosfina, no seio de 100 mL de THF, adicionou-se 28,3. mmole de azodicarboxilato de di-terc-butilo e agitou-se a mistura à TA, durante 90 minutos. Concentrou-se então a mistura in vacuo, para se obter o composto do titulo. EM (m/e) : 237,1 (M+H+, 100 %) (b) Ácido 5-acetil-2-isopropoxi-benzóico A 25,8 mmole do éster metilico do ácido 5-acetil-2-isopropoxi-benzóico,. no seio de 100.mL de THF, adicionou-se 4 00 mmole de NaOH aquoso 2 .M e aqueceu-se a mistura a 80 °C, durante 2 horas. Arrefeceu-se então a mistura, para a TA e extraiu-se 2 vezes com éter. Acidificou-se a fase aquosa com ácido clorídrico aquoso a 15 % e extraiu-se 3 vezes com acetato de etilo.. Secaram-se as fases orgânicas combinadas com Na2SC&gt;4. A evaporação in vacuo seguida de trituração no seio de éter, originou o composto do título. .EM (m/e): 221,2 ([M-H]&quot;, 100 %) 167 i Em analogia com o exemplo 5, prepararam-se os i compostos 472 a 619 do quadro que se segue, a partir dos j derivados de ácido e derivados de piperazina:Preparation of 5-acetyl-2-isopropoxy-benzoic acid (a) 5-Acetyl-2-isopropoxy-benzoic acid methyl ester To 25.8 mmol of methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol of 2- propanol and 29.6 mmol of triphenylphosphine in 100 mL of THF added 28.3. of di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 90 minutes. The mixture was then concentrated in vacuo to give the title compound. (B) 5-Acetyl-2-isopropoxy-benzoic acid To 25.8 mmol of 5-acetyl-2-isopropoxy-benzoic acid methyl ester ,. in 100 ml of THF was added 400 m aq. of 2M aqueous NaOH and the mixture was heated at 80 ° C for 2 hours. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 15% aqueous hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4. Evaporation in vacuo followed by trituration in ether afforded the title compound. 1 H-NMR (m / e): 221.2 ([MH] &quot;, 100%) In analogy to example 5, compounds 472 to 619 of the following table were prepared from the derivatives of acid and piperazine derivatives:

Exemp.. N°. Nome Sistemático Materiais Iniciais PM encont. (M+H) 472 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-1-carbonil]-4-etoxi-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-etoxi-5-sulfamoil-benzóico (patente de invenção JP 53050139) 433,2 473 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4-etoxi-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-etoxi-5-sulfamoil-benzóxcQ (patente de invenção JP 53050139) 431,3 (M-H) 474 3-[4-(4-ciano-fenil)- piperazino-l-carbonil]-4- etoxi-benzeno-sulfonamida 4-piperazin-l-iÍ-beúzonitrilo (comercial) e ácido 2-etoxi-5-sulfamoil-benzóico (patente de invenção JP 53050139) 413,3 (M-H) 475 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4-isobutoxi-N-metil-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-isobutoxi-5-metilsulfamoil-benzóico (composto 6.1) 475,1 476 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carboníl]-4-(2,2-dimetil-Propoxi)-N-metil-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il~ benzonitrilo (patente de invenção WO 9808835)· e ácido 2-(2,2-dimetil-propoxi) -5-metilsulfamoil-benzóico (composto 6.2) 489,3 477 3- [4- (4-c.iano-3-fluoro-fenil)-piperazino-1-carbonil]-4-isopropoxi-N-metil-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-ben-zonitrilo (patente de invenção WO 9808835) e ácido 2-isopro-poxi-metilsulfamoil-benzóico (composto 6.3) 461,2 478 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4-ciclopentiloxi-N-metil-benzeno-sulfònairiida 2-fluoro-4-piperazin-l-il-ben-zonitrilo (patente de invenção WO 9808835) e ácido 2-ciclopen-tiloxi-5-metilsulfamoil-benzóico 487,3 168 (composto 6.4) 479 3- [4- (4-ciano-3-fluoro-fenil)-piperazino-l-carbonil] -4-ciclobutoxi-N-metil-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclobutoxi-5-metilsulfamoil-benzóico (composto 6.5) 473,1 480 3- [4- (4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4- ciclopropilmetoxi-N-metil- benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclopropilmetoxi-5-metilsulfamoil-benzóico (composto 6.6) 473,2 481 3- [4- (4-ciano-3-fluoro- fenil)-piperazino-l- carbonil)-4- ciclobutilmetoxi-N-metil- benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-ciclobutilmetoxi-5-metilsulfamoil-benzóico (composto 6.7) 487,3 482 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil] -N-metil-4-(tetra-hidro-piran-4-iloxi)-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-etilsulfamoil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 6.8) 503,2 483 3-[4-(4-ciano-3-fluoro-fenil}-piperazino-1-carbonil]-4-(2-metoxi-etoxi)-N-metil-benzeno- sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 2-(2-metoxi-etoxi)-5-metilsulfamoil-benzóico (composto 6.9) 477,3 484 3- [4- (4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-N-metil-4-(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835) e ácido 5-metilsulfamoil-2-(3,3,3-trifluoro-propoxi)-benzóico. (composto 6.10) 515,2 485 3- [4-(4-ciano-fenil)-piperazino-l-carbonil]-4-(2-metoxi-etoxi)-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-(2-metoxi-etoxi)-5-metilsulfamoil-benzóico (composto 6.9) 459,1 . 486 3- [4- (4-ciano-fenil)-piperazino-l-carbonil]-N-metil-4-(3,3, 3-trifluoro-propoxi)-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 5-metilsulfamoil-2- (3., 3,3-trifluoro-propoxi)-benzóico (composto 6.10) 497,0 169 487 3- [4- (4-ciano-fenil)-piperazino-l-carbonil)-N-metil-4-(tetra-hidro-piran- 4- iloxi)-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 5-metilsulfamoil-2-(tetra-hidro-piran-4-iloxi)-benzóico (composto 6.8) 485,2 488 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-isobutoxi-N-metil-benzeno-sulfonamida 4- piperazin-l-il-benzonitrilo (comercial) e ácido '2-isobutoxi- 5- metilsulfamoil-benzóÍco (composto 6.1) 457,3 489 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-(2,2-dimetil-propoxi)-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonit ri1o (comercial) e ácido 2-(2,2-dimetil-propoxi)-5-metilsulfamoil-benzóico (composto 6.2) 471,1 • 490 3- [4-(4-ciano-fenil)-piperazino-l-carbonil]-4-isopropoxi-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2— isopropoxi-5-metilsulfamoil-benzóico (composto 6.3) 443,2 491 3- [4- (4-ciano-fenil)-piperazino-l-carbonil]-4-ciclopentiloxi-N-inetilbenzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-ciclopentiloxi-metilsulfamoil-benzóico (composto 6.4) 469,2 492 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-ciclobutoxi-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-ciclobutoxi-5-etilsulfamoil-benzóico (composto 6.5) 455,3 493 3-[4-(4-cíano-fenil)-piperazino-l-carbonil]-4-ciclopropilmetoxi-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 2-ciclopropilmetoxi-5- metilsulfamoil-benzóico (composto 6.6) 455,3 494 3-[4-(4-ciano-fenil)-piperazino-l-carbonil]-4-ciclobutilmetoxi-N-metil-benzeno-sulfonamida 4-piperazin-l-il-benzonítrilo (comercial) . e ácido 2-ciclobu-tilmetoxi-5-metilsuífamoil-benzóico (composto 6.7) 469,2 495 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-isobu-toxi-N-metil-benzeno-sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-isobutpxi-5-metllsul-famoil-benzóico (composto 6.1) 528,0 . 496 4- (2,2-dimetil-propoxi)-3-[4-(2-fluoro-4-metano-snlfonil-fenií)-piperazino-l-carbonil) -N-metil- 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-(2,2-dimetil-propoxi)-5-metilsulfamoil-benzóico 559,2 (M+NH/) 170 benzeno-sulfonamida (composto 6.2) 497 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-4-benzeno-sulfonamida 1- (2-fluoro-4-metano-sUl£onil-fenil)-piperazina (comercial) e ácido 2-isopropoxi-5-metilsulfamoil-benzóíco (composto 6.3) 514,1 4 93 4-ciclopentiloxi-3-[4-(2-fluoro-4-metaho-sulfo'nil-fenil)-piperazino-1-carbonil]-N-metil-benzeno-sulfonaraida 1- (2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e. ácido 2-ciclopentiloxi-5-metilsulfamoil-benzóico (composto 6.4) 557,0 (M+NH4+) 499 4-ciclobutoxi-3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-N-metil-benzeno-sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclòbutoxi-5-metilsulfamoil-benzóico (composto 6.5) 526,0 500 4-ciclopropllmetoxi—3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonilJ-N-metil-benzeno-sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclopropilmetoxi-5-etilsulfamoil-benzóico (composto 6.6) 526,0 501 4-ciclobutilmetoxi-3-[4-(2-fluoro-4-metano-sulfonil-fenil}-piperazino-1-carbonil]-N-metil-benzeno-sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclobutilmetoxi-5-metilsulfamoil-benzóico (composto 6.7) 557,0 (M+NH4+) 502 3-[4-(2—fluoro-4-metanq-sulfonil-fenil)-piperazino-l-carbonil]-4-(2-metoxi-etoxi)-N-metil-benzeno-' sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-(2-metoxi-etoxi)-5-metilsulfamoil-benzóico (composto 6.9) 530,1 503 3-[4-(2-fluoro-4-metano-sulfon.il-fenil) -piperazi-na-l-carbonilj—N-metil-4-(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida 1- (2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metilsulfamoil-2-(3,3,3-trifluoro-propoxi)-benzóico (composto 6.10) 585, 0 (M+NH4+) 504 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-1-carboníl]-4-isobutoxi-N-metil-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il-ben-zonitrilo (patente de invenção WO 9625414) e ácido 2-isobu-toxi-5-metilsulfamoil-benzóico (composto 6.1) 475,0 505 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-1-carbonil]-4-(2,2-metil-propoxi)-N-metil-benzeno- 3-fluoro-4-piperazin-l-il-. benzonitrilo (patente, de invenção WO 9625414) e ácido 2(2,2-dimetil-propoxi)-5- 489,0 171 sulfonamida metilsulf ainoil-benzóico (composto 6.2) 506 3-[4-(4-ciano-2-fluoro- fehil)-piperazino-1-carbonil]-4~isopropoxi-N-metil-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-isopropoxi-5-metilsulfamoil-benzóico (coniposto 6.3) 478,0 (M+NH/) 507 3-[4-(4-ciano-2~fluoro-fenil)-piperazino-1-carbõnil]-4-ciclopentiloxi-N-metil-benzeno-sulfonamida 3-fluóro-4-piperazin-l-il-benzonitrilo (patente de invenção. WO 9625414) e ácido 2-ciclopentiloxi-5-metilsulfamoil-benzóico (composto 6.4) 487,1 508 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-1-carbonil]-4-ciclobutoxi-metil-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido ciclobutoxi-5-metilsulfamoil-ben2óico (composto 6.5) 472,8 509 3-[4-(4-ciano-2-fluoro- fenil)-piperazino-1-carbonil]-4- ciclopropilmetoxi-N-metil-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il- benzonitrilo (patente de invenção WO 9625414} e ácido 2-ciclopropilmetoxi-5-metilsulfamoil-benzóico (composto 6.6} .472,8 510 3-(4-(4-ciano-2-fluoro-fenil)-piperazino-1-carbonil]-4- ciclobutilmetoxi-N-etil-benzeno-sulfonamida 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-ciclobutilmetoxi-5-metilsulf ainoil-benzóico (composto 6.7) 487,1 511 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-1-carbonil]-N-metil-4-(tetra-hidro-piran-4-iloxi)-benz eno-sulfonamida 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-etilsulfamoil-2-(tetra-hidro-5-piran-4-iloxi)-benzóico (conposto 6.8) 503,0 512 3-[4-(4-çiano-2-fluoro-fenil)-piperazino-1-carbonil]-4-(2-metoxi-etoxi)-N-metil-benzeno-sulfonamida 3-fluoro-4-pipe ra z in-1-i1-ben-zonitrilo (patente de invenção WO 9625414} e ácido 2-(2-metoxi-etoxi)-5-metilsulfamoil-benzóico (composto 6.9) 477,1 513 3-[4-(4-ciano~2-fluoro-fenil)-piperazino-1-carbonil]-N-metil-4-(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida 3-fluoro-4-piperazin-1-il-benzonitri.lo (patente de invenção WO 9625414) e ácido 5-metilsulfamoil-2-(3,3,3-trifluoro-propoxi)-benzóico 515,1 172 (composto 6.10) 514 3- [ 4- (4-acetil-2-f luor.o-fenil)-piperazino-1-carbonil]-4-isobutoxi-N-metil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção W0 9714690) e ácido 2-isobutoxi-5-metilsulfainoil-benzóico (composto 6.1) 492,1 515 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-1-carbonill-4-(2,2-dimetil-propoxi)-N-metil-benzeno-sulfonamida 1-(3-£luorp-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-(2,2-dimetil-propoxi)-5-metilsulfamoil-benzóico (composto 6.2) - 506,3 516 3^ [4-(4-acetil-2-fluòro-fenil)-piperazino-l-carbónil]~4~isopropoxi-N~ métil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-.i s opropoxi-5-met i1sulf amoii-benzóico (composto 6.3) 478,2 517 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-1-carbonil)-4-ciclopentiloxi-N-metil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-ciclopentiloxi-5-metilsulfamoil-benzóico (composto 6.4) 504,2 518 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-l-carbonil]-4-ciclobutoxi-N-metil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-ciclobutoxi-5-metilsulfamoil-benzóico (composto 6.5) 590, 6 519 3-[4-(4-acetil-2-fluoro- fenil)-piperazíno-l- carbonil]-4- ciclopropilmetoxi-N-metil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 2-ciclopropilmetoxi-5-metilsulfamoil-benzóico (composto 6.6) . 490,2 520 3-[4-(4-acetil 2-fluoro- fenil)-piperazino-l- carbonil]-4- ciclobutilmetoxi-N-metil-benzeno-sulfonamida 1- (3-fluoro-4-piperazin-l-il-fenil)-etanona (patente de invenção WQ 9714690) e ácido 2-ciclobutilmetoxi-5-metilsul-famoil-benzóico (composto 6.7) 504,2 521 3-[4-(4-acetil-2-fluoro-fenil)-piperazino-1-carbon.il] -N-metil-4- (tetra-hidro-piran-4-iloxi)-benzeno-sulfonamida 1- (3-fluoro-4-píperazin-l-il-fenil)-etanona (patente de invenção WO 9714690) e ácido 5-metilsulfaitioil-2- (tetra-hidro-piran- 4-iloxi)-benzóico (composto.6.8) 520,3 173 522 3- [4- (4-acetil-2-fluoro~ fenil)-piperazino-l-carbonil] -4- (2-metoxi-etoxi)-N-metil-benzeno-sulfonamida 1-(3-fluoro-4-piperazin-l-il-fenil)-etanofta (patente de invenção WO 9714690) e ácido 2-(2-metoxi-etoxi)-όπιά tilsulfamoil-benzóico (composto 6.9) 494,2 523 3- [4- (4-acetil-2-fluoro-fenil)-piperazino-1-carbonil]-N-metil-4(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida 1-(3-fluoro-4-pipera2Ín-il- . fenil)-etariona (patente de invenção WO 97146Ô0) e ácido 5-metilsulfamoil-2-(3, 3,3-trifluoro-propoxi)-benzóico (composto 6.10) 532,2 524 4-isobutoxi-N-metil-3-[4-(4-trifluorometil-fenil) -piperazinò-l-carbonil]-benzeno-sulfonainida 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2- isobutoxi-5-metilsulfamoil-benzóico (composto 6.1) 500,2 525 4-(2,2-dimetil-{4 ~(4 — trifluorometil-[4-(4-trifluorometil-fenil) -piperazino-1]-carbonil]-benzeno-sulfonamida 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2- (2,2-dimetil-propoxi)-5-metilsuífamoil-benzóico (composto 6,2) 514,2 526 4-isopropoxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazino-l-ca.rbonil] -benzeno-sulfonamida 1- (4-trifluorometil-fenil)-piperazina (comercial) é ácido 2- isopropoxi-5-metilsulfamoil-benzóico (composto 6.3) 486,2 527 4-ciclopentiloxi-N-metil-3-[ 4-{4-trifluorometil-fenil)-piperazino-1-carbonil]-benzeno-sulfonainida 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2- ciclopentiloxi-5-metilsulfamoil-benzóico ' (composto 6.4.) 512,3 528 4-cÍclobutoxi-N-etil-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzeno-sulfonainida 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2- ciclobutoxi-5-metilsulfamoil-benzóico (composto. 5.5) 498,2 529 4-ciclopropilmetoxi-N-itietil-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzeno-sulfonamida 1- (4-trifluorometil-fenil)-piperazina (comercial) e ácido 2- ciclopropilmetoxi-5-metilsulfamoil-benzóico (composto 6.6) 498,2 530 4-ciclobutilmetoxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil] -benzeno-sulfonamida 1- (4-trifluorometil-fenil)-piperazina· (comercial) e ácido 2- ciclobutilmetoxi-5-metilsulfamoil-benzóico (composto 6.7) 512,3 531 N-metil-3-[4-(4- 1-(4-trifluorometil^fenil)- 540,2 174 trifluorometil-fenil)-piperazino-l-carbonil]-4-(3,3,3-trifluoro-propoxi)-benzeno-sulfonamida piperazina (comercial) e ácido 5-etilsulf amoil-2-.(3, 3,3-trifluoro-propoxi)-benzóico (composto .6.10) 532 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil] -N-metil-4-(2,2,2-trifluoro-etoxi)-benzeno-sulfonamida... 2-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9808835).e ácido 5-metilsulfamoil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 6.11) 501,1 533 3-[4—(4-ciano^fenil) -piperazino-l-carbonil] -N-metil-4-(2,2,2-trifluoro-etoxi ) benzeno-sulfonamida 4-piperazin-l-il-benzonitrilo (comercial) e ácido 5-metilsulfamoil-2- (2,2,2-trifluoro-etoxi)-benzóico (composto 6.11) 483,3 534 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil] -N-metil-4-(2,2,2-trifluoro-etoxí)-benzeno-sulfonamida 3-flúoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-metilsulfamoil-2-(2,2,2-' trifluoro-etoxi)-benzóico (composto 6.11) 501, 1 535 3-[4-(4-acetil-2~fluoro-fenil)-piperazino-l-carbonil] -N-metil-4-(2,2,2-trifluoro-etoxi)-benzeno-sulfonamida 1- (3-fluoro-4-piperazin~l~il-fenil)-etanona (patente de invenção WO 9714690) e ácido 5-metilsulfamoil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 6.11) 518,2 536 3- [4- (2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-N-metil-4-(2,2,2-trifluoro-etoxi)-benzeno-sulfonamida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 5-metilsulfamoil-2-(2,2,2-trifluoroetoxi)-benzóico. (composto 6.11) 554,1 537 N-Metil-4-(2,2,2-trifluoro-etoxi) -3- [4-{4-trifluorometil-fenil)-piperazino-l-carbonil]-benzeno-sulfonamida 1-(4-trifiuorometil-fenil) -piperazina (comercial) e ácido. 5-etilsulfamoil-2-(2,2,2-trifluoro-etoxi) benzóico (composto 6.11) 526,0 538 [4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-1-il]-(2-sopropoxi-5-metano-sulfonil'-f énil-metanona 1-(4-etano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 513,3 175 539 {4-[4-(butano-l-sulfonil)-2-fluoro-2-lsopropoxi-5-metano-sulfonil-fenil·} -metanona 1- [4- (butano-l-sulf on.il) -2-fluoro-fenil]-piperazina (composto 6.13) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 541,0 540 4-[4-(5-ciclopropano-sulf onil- 2 -is opropoxi-benzoil)-piperazin-l-il]-3-fluoro-benzonítrilo 3-fluoro-4-piperazin-l-il-benzonitrilo .(patente de intenção WO 9625414) e ácido 5-cicloprópano-sulfonil-2-isopropoxi-benzóico (composto 6.14) 472,3 541 (5-ciclopropano-sulfonil-2-isopropóxi-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-ilj-etanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 5-ciçlopropano-sulfonil- 2- isopropoxi-benzóico (composto 6.14) 515,4 542 (5-ciclopropano-sulfonil-2-isobutoxi-fenil)-[4-(2-fluoro-4-metanõ-sulfonil-fenil)-piperazin-l-il]- metanona 1-(2-fluoro-4-metano-sulfonil-fenil.)-piperazina (comercial) e ácido 5-cicloprópano-sulfonil-2-isobutoxi-benzóico (composto 6.15) 539,5 543 4- [4-(5-ciclopropano-sulf onil-2-isobutoxi-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo 3-fluoro-4-piperazin-l—il-benzonitrilo (patenté de invenção WO 9625414) e ácido 5-ci-clopropano-sulfonil-2-isobu-toxi-benzóico (composto 6.15} 486,5 544 (5-ciclopropano-sulfonil-2-isobutoxi-fenil) - [4-.(2-fluoro-4-trifluorometil-fenil)-píperazin-l-il]-metanona 1- (2-fluoro 4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 5-ciclopropano-sulfonil- 2- isobutoxi-benzóico (composto ..6.15) ' 529,4 545 ' .(2-ciclopentiloxi-5-ciclopropano-s.ulfonil-fenil)-[4-'(2-f Íuoro-4-metano-sulfonil-fenil) -piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclopentiloxi~5-ciclopropano-sulfonil-benzóico (composto 6.16) 551,3 546 4-[4-(2-ciclopentiloxi-5-ciclopropano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzoiiitrilo 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 2-ciclopentiloxi-5-ciclopropano-sulfonil-benzóico (composto’ 498,3 176 6.16) 547 (2-ciclopentiloxi-5-ciclopropano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composto 1.1) e ácido 2-c±clopentiloxi-5-ciclopropano-sulfonil-benzóico (composto 6.16) 541,3 543 (5-ciclopropano-sulfonil-2-ciclopropilmetoxi-fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-1-il]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil-piperazína (comercial) e ácido 5-ciclopropano-sulfonil-2-ciclopropilmetoxi-benzóico (composto 6.17) 537,4 ,549 4—[4—(5-cicloprcpano-sulfonil-2- ciclopropilmetoxi-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo. 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção WO 9625414) e ácido 5-ciclopropano-sulfonil-2-ciclopropilmetoxi-benzóico (composto 6.17) . 484,5 550 (5-ciclòpropano-sulfonil-2-ciclopropilmetoxi-fenil)-[4-(2-fluoro-4-trifluorometil fenil)-piperazin-l-il]-metanona 1- (2-fluoro-4-trifluorometil-fenil)-piperazina (composta 1.1) e ácido 5-ciclopropano-sulfonil- 2- ciclopropilmetoxi-benzóico (composto 6.17) 527,3 551 (2-ciclobutoxi“5-ciclopropano-sulfonil-fenil)-(4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido 2-ciclobutoxi-5-ciclopropano-sulfonil-benzôiço (composto 6.18) 537,4 552 (5-ciclopropano-sulfonil-2-isopropoxi-fenil)-[4-(2-fluoro-4-metano-sulfoníl-fenil·) -piperazin-l-il] -metanona 1-(2-fluoro-4-metano-sulfonil-fenil)'-piperazina (comercial) e ácido 5-ciclopropano-sulfonil-2-isopropoxi-benzóico (composto 6-14) 525,3 553 rac-3- [.4- (2-fluoro-4-meta-no-sulfonil-fenil)-pipera-zino-l-carbonil]-N-metil-4-(2,2,2-trifluoro-l-me-til-etoxi)-benzeno-sulfo-namida 1-(2-fluoro-4-metano-sulfonil-fenil)-piperazina (comercial) e ácido rac-5-metilsulfamoil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 6.19) 585,1 (M+NH/) 554 rac-N-metil'-4- (2,2,2-tri-fluoro-l-metil-etoxi)-3-[4-(4-trifluorometil-fe-nil)-piperazina-l-carbo-nil]-benzeno-sulfonamida l-(4-trifluorometil-fenil)-piperazina (comercial) e ácido rac-5-metilsulfamoil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto. 6.19) 557,2 (Κ+ΝΗ4+) 555 rac-3-[4-(4-ciano-2-fluoro- 3-fluoro-4-piperazin-l-il- 532,3 177 fenil)-piperazino-1-carbonil]-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi)-benzeno-sulfonamida benzonitrilo (patente de invenção WO 9625414) e ácido rac-5-metilsulfamoil-2-(2,2,2-triffuoro-l-metil-etoxi)-benzóico (composto 6.19) (M+NH/) 556 [4-(4-ciclopropano-sulfonil-2-f luoro-fenil.)-piperazin-l-il]-(2- . isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(4-ciclopropano-sulfonil-2~ fluoro-fenil)-piperazina (composto 6.20) e ácido 2— isopropoxi-5-metãno-sulfonil-benzóico (composto 1.2) 542,2 (M+NH4+) 557 rac-3-[4-(4~ciano-2,5-difluoro-fenil)-piperazino-1-carbonil]-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi)-benzeno-sulfonamida ácido 2, 5-difluoro-4-piperazin-1-il-benzonitrilo-trifluoro-acético (composto 2.8) e ácido rac-5-metilsulfamoil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 6.19) 550,1 (M+NH4+) 558 rac-3-[4-(4-ciano-2,3-difluoro-fenil)-piperazino-1-carbonil]-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi) -benzeno-sulfonamida ácido 2,3-difluoro-4-piperazin-1-il-benzoiii trilo-trif luoro-acético (composto 2.7) e ácido ràc-5-metilsulfamoil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 6.19) 550,1 (M+NH/) 559 {4-(2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il}-(2-isopropoxi-5-metano-sulfonil-fenil}-metanona 1-[2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.21) e ácido 2-isopropoxi-5-metano-sulfonil-benzóioo (composto 1.2) 544,3 (M+NH/) . 560 [4-(4-ciclopropilmetano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-(2-fluoro-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1- (4-cíclopropilmetano-sulfonil- 2- fluoro-fenil)-piperazina (composto 6.22) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 556,2' . (M+NH4+') 561 {4- [2-fluoro-4-(2-metoxi-etano-sulfonil)-fenil]-. piperazin-l-il}-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-[2-fluoro-4-(2-metoxi-etano-sulfonil)-fenil]-piperazina (composto 6.23) e ácido 2-isopropoxi-5-metano-sulfonil-benzóíco (composto ,1.2) 5 60,3 (M+NH/) 562 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil) -piperazin-l-il]-metanona 1- (4-etano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2- ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 542,2 (M+NH4+) 563 (2-ciclopentiloxi-5-metano-sulfonil-penil)-[4-(4-4- . 1-(4-etano-sulf.onil-2-fluoro-fenil) -piperazina (composto 556,1 (M+NH4+) 178 etano-sulfonil-2-fluoro-fenil)-piperazin-l-Il]- metanona 6.12) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) .564, (2-ciclo-hexiloxi^5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona 1-(4-ètano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2-ciclo-hexiloxi-5-metano-sulfohil-benzóico ; (composto 3.2) 570,2 . (M+NH„+) 565 [2-(2, 2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(4-et ano-sulfoni1-2-fluoro-fenil)-piperazin-l-il]-metanona 1-(4-etano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2-(2,2-dimetil-propoxi) -5-metano-sulfonil-benzóico (composto 3.3) 558,2 (M+NH4+) 566 [4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il] - (2-isobutoxi-5-metano-sulfonil-fenil)-metanona 1- (4-etano-s-ulfonil-2-fluoro-f enil (.-piperazina (composto 6.12) e ácido 2-isobutoxi-5-metano-sulfonil-benzóico (composto 1.3) 544,2 (M+NH4+) . 567 (2-ciclobutoxi-5-metano-Sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-f enil.) -piperazin-l-il] -metanona 1_(4-etano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 542,3 (M+NH/) 568 rac-(2-sec-butoxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona 1-(4-etano-sul£onil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido rac-2-sec-butpxi-5-metano-sulfonil-benzóico (composto 3.5) 544,2 (M+NH4+) . 569 (2-ciclobutilmetoxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]- metanona 1-(4-etano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.12) e ácido 2-ciclobutilmetoxi-5-metano-sulfonil-benzóico (composto 2.12) . 556,1 (M+NH4+) 570 [4-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil)- metanona cloridrato de 1-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.24) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 556,1 (M+NH4+) . 571 [4-(4-ciclopentanesulfonil-2-fluoro-fenil)-piperazin- cloridrato de 1-(4-ciclopentano-sulfonil-2-fluoro-fenil)- 570,3 (M+NH4+) 179 1-il]-(2-isopropoxi-5-metano-sulfonil-fenil) -metanona piperazina (composto 6.25) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 572 [4 -(4-ciclopropano-sulfonil-2-fluoro-Fenil)-piperazin-l-il]-(2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-metanona 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-cic1opropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 537,2 573 (2-ciclopentiloxi&quot;5-metano-sulfonil-fenil)-[4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il] -metanona 1- (4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-ciclopentiloxi-5-metano-sulfonil-benzóico (composto 1.6) 568,0 (M+NH4+) 574 (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il] -metanona 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-ciclo-hexiloxi-5-metano-sulfonil-benzóico (composto 3.2) 582,1 (M+NH/) 575 [4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-metanona 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-(2,2-di-metíl-propoxi)-5-metano-sulfo-nil-benzóico (composto 3.3) 570,2 (M+NH4+) 576 (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il ]-metanona 1-(4-ciclopropano~sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-ciclobutoxi-5-metano-sulfonil-benzóico (composto 3.4) 536,9 577 {4- (2-fluoro-4- (3,3,-3-tri-fluoro-propano-l-sulfo-nil)-fenil]-piperazin-l-il}- (2-isopropoxi-5-meta-no-sulfonil-fenil)-metanona 1-[2-fluoro-4-(3,3,3-trifluoro-propàno-l-sulfonil)-fenil]-piperazina (composto 6.26) e ácido 2-isopropoxi-5-metano-sulfo-nil-benzóico (composto 1.2) 581,0 578 [4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonll-fenil)-metanona 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20) e ácido 2-i s obutoxi-5-metano-sulfoni1-benzóico (composto 1.3) 556,1 (M+NH4+) 579 {4-(2-fluoro-4-(tetra-hidro-piran-4-sulfonil)-fenil] -piperazin-l-il'} - (2-isopropoxi-5-metano-sulfonil-fenil)-metanona 1-(2-fluoro-4-(tetra-hidro-piran-4-sulfonil)-fenil]-piperazina (composto 6.27) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 586,2 (M+NH4+) 580 (2-terc-butoxi-5-metano-sulfonil-fenil) --[4-[2- 1-[2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazina 558,2 (M+NH4+) 180 fluoro-4-(propano-2-sulfonil}-fenil]-piperazin-l-il } -metanona (composto 6.21) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 581- (2-1erc-butoxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluorofenil)-piperazin-1-il]-metanona 1- (4-etano-sulfonil-2-fluoro-fen.il)-piperazina (composto 6.12) e ácido 2-terc-butoxi-.5-metano-sulfonil-benzóico (composto 2.19) 544,2 (M+NH/) 582 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-1-il]-metanona 1- (4-ciclopropano-sulfonil-2-fluorofenil)-piperazina (composto 6.20) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 556,1 (M+NH/) 583 {4-[2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazin-1-il}-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1-[2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.21) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 584,1 &lt;M+NH4+) 584 [4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona 1- (4-etano-sulfonil-2-fluorofenil) -piperazina (composto 6.12) e ácido 5-metano-sulfonil- 2- (2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 570,3 (M+NH/) 585 [4-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-[5-metano-sulfónil-2-(2,2,2-trifluoro-etoxi)-fenil] -metanona 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.20} e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 582,1 (M+NH4+) 586 rac-{4-[2-fluoro-4-(propano-2-sulfonil)-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona 1-[2-fluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.21) e ácido rac-5-metano-sulfonil-2-(2, 2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 598,2 (M+NH4+) 587 rac-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l-me-til-etoxi)-fenil]-metanona 1-(4-fenil)-2-fluoro-fenil)-piperazina (composto 6.12) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 584,1 (M+NH/) 588 rac-[4-(4-ciclopropano-sulfonil-2-fluoro-fenil)- 1-(4-ciclopropano-sulfonil-2-fluoro-fenil)-piperazina (com- 596,2 (M+NH4+) 181 piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona posto 6.20) e ácido rac-5-me-tano-sulfonil-2-(2,2,2-trifluo-ro-l-metil-etoxi)-benzóico (composto 3.1) 589 [4-(4-ciclo-h0xano-. sulfonil-2-fluoro-feníl}-piperazin-l-il]-(2-isopropoxi-5-Inetano-sulfonil-fenil)-metanona 1-(4-ciclo-hexano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.28) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 584,3 (M+NlO 590 {4-[2,3-difluoro-4-(propano-2-sulfonil)-fenil)-piperazin-l-il}-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona cloridrato de 1-[2,3-difluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.29) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 545,2 591 [4-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazin-1-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona cloridrato de 1-(4-etano-sulfo-nil-2,3-difluoro-fenil)-pipe-ra-zina (composto 6.30) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 531,1 592 (4-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona cloridrato de 1-(4-ciclopro-pa-no-sulfonil-2,3-difluoro-fe-nil)-piperazina (composto 6.31) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 543,3 593 {4-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il)-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona cloridrato de 1-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazina (còmposto 6.32) e á-cido 2-isopropoxi-5-metano-sul-· fonil-benzóico (composto 1.2) 545,2 594 ' [4- (4-etano-sulfonil-2,5-difluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-' metano-sulfonil-fenil)-metanona cloridrato de 1-(4-fenil)-2,5-difluoro-fenil)-piperazina (composto 6.33) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 531,1 . 595 [4- (4-ciclopropano-sulfonil-2,5-difluoro-fenil)-piperazin-l-il] -(2-isopropaxi-5-metano-sulfonil-fenil)-metanona cloridrato de 1-(4-cicloprcpano-sulfonil-2,5-difluoro-fenil)-piperazina (composto 6.34) e ácido 2-isopropox±-5-metano-sulfonil-benzóico (composto 1,2) 543,3 596 {2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-ciclobutano-sulfonil'-2-fluoro-fenil)-piperazin-l-il] -metanona . cloridrato de 1-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazina (composto 6.24).e ácido 2-terc-butoxi-5-metano-sulfo-nil-benzóíco (composto 2.19) 553,6 597 (2-terc-butoxi-5-metano- cloridrato de 1-[2,3-difluoro-4- 503,1 182 sulfonil-fenil)-(4-(2,3-difluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il) -me t anona (propano-2-sulfonil)-fenil] -piperazina (composto 6.29) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) .(M-tBu+H) 598 (2-terc-butoxi-5-metano~ sulfonil-fenil)-[4-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazin-l-il] -métanona cloridrato de 1- (4-etano-sul-f onil-2,3-di.f luoro-f enil) -piperazina (composto 6.30) e ácido 2-terc-butoxi-5-metano-sulfó-nil-benzóico (composto 2.19) 489,2 (M-tBu+H) 599 ; (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazin-l-il;] -métanona cloridrato de 1-(4-ciclopropa-no-sulfonil-2,3-difluoro-fe-nil)-piperazina (composto 6.31) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 501,1 (M-tBu+H) 600 (2-terc-butoxi-5-metano-sulfonil-fenil)-(4-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazin-1-il}-métanona cloridrato de 1-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.32) e ácido 2-terc-butoxi-5-metano-sulfonil-benzóico (composto 2.19) 503,2 (M-tBu+H) 601 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-eta-no-sulfonil-2,5-difluoro-fenil)-piperazin-l-il]-métanona cloridrato de 1-(4-etano-sul-fonil-2,5-difluoro-fenil)-piperazina (composto 6.33) e ácido 2-terc-butoxi-5-metano-sulfo-. nil-benzóico (composto 2.19) 489,1 (M-tBu+H) 602 (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(4-, ciclopropano-sulfonil-2,5-difluoro-fenil)-piperazin-l-il] -métanona cloridrato de 1-(4-ciclopropano-sulfonil-2,5-difluoro-fenil)-piperazina (composto 6.34) e ácido 2-terc-butoxi-5-metano- sulfonil-bènzóico (composto 2.19) 501,3 (M-tBu+H) 603 [4-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trif luor.o-etoxi) -fenil]-métanona cloridrato de 1-(4-ciclobutano-sulfonil-2-fluoro-fenil)- piperazina (composto 6.24) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 579,1 604 (4-[2,3-dÍfluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il}-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]- cloridrato de. 1-[2, 3-difluoro-4-(propano-2-sulfonil)-fenil] -piperazina (composto 6;29}'e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico 602,2 (M+NH4+) 183 metanona (composto 1.5) 605 [4-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazin- 1- il]- [5-metano-sulfonil-2- 2- (2,2,2-trifluoro-etoxi)-fenil]-metanona cloridrato de l-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazina (composto 6.30) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 571,2 606 [4-(4-ciclopropano-sulfoníl-2,3-difluoro-fenil) -piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluóro-etoxi)-fenil]-metanona cloridrato de 1-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazina (composto 6.31) e. ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 600,2 (M+NH4+) 607 (4-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il}-[5-m.etano-sulfonll-2- (2,2,2-trifluoro-etoxi) fenil]-metanona cloridrato de 1-[2,5-difluoro-4™ (propano-2-sulfonil)-fenil]-piperazina (composto 6.32) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 602,3 (M+NH4+) 608 [4-(4-etano-sulfonil-2,5-difluoro-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona cloridrato de l-(4-etano-sulfonil-2,5-difluoro-fenil)-piperazina (composto 6.33) e ácido 5-metano-sulfonil-2-(2,2,2-:trifluoro-etoxi) -benzóico {composto 1.5) 588,3 . (M+NH/) 609 [4-(4-ciclopropano-sulfonil-2,5-difluoro-fenil) -piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-e.toxi) -fenil-metanona cloridrato de 1-(4-ciclopropano-sulfònil-2,5-difluoro-fenil)-piperazina (composto 6.34) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 600, 2 (M+NH/) 610 rac-[4-(4-ciclobutano- sulfonil-2-fluoro-fenil)- piperazin-l-il]-[5-metano- sulfonil-2-(2,2,2- trifluoro-l-metil-etoxi)- fenil-metanona cloridrato de 1-(4-ciclobutano-suIfonil-2-fluoro-fenil) -piperazina (composto 6.24) e ácido rac-5-metano-sulfonil-2-(2, 2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 593,2 611 rac-{4-[2,3-difluoro-4- · (propano-2-sulfonil)-fenil]-piperazin-l-il}-[5-metano-sulfonil-2-(2,2,2- cloridrato de 1-(2,3-difluoro-4-(propano-2-sulfonil)-fenil)-piperazina (composto 6.29) e ácido rac-5-metano-sulfonil-2- 599,2 184 trifluoro-l-metil-etoxi)-fenil]-metanona (2,2,2-trifluoro-l-metil-etoxi) -benzóico (composto 3.1) 612 rac-[4-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazin-1-il]-[5-metano-súlfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona cloridrato de l-(4-etano-sulfonil-2,3-difluoro-fenil)-piperazina (composto 6.30) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 602,2 (M+NHa+) 613 rac-[4-(4-ciclopropano-sulfonil-difluoro-fenil)-6.31) e piperazin-l-il]-[5-metano-sul£onil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona cloridrato de 2,3-1-(4-ciclopropano-sulfonil-2,3-difluoro-fenil)-piperazina (composto 6.31) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -benzóico (composto 3.1) 614,3 (M+NIl/) 614 rac-4-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazin-l-il}-{5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona cloridrato de- 1-[2,5-difluoro-4-(propano-2-sulfonil)-fenil]-piperazina (composto 6.32) e ácido rac-5-metano-sulfonil-2-(2, 2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 616,2·.' (M+NH/) 615 rac-[4-(4-etano-sulfonil-2,5-difluoro-fenil)-piperazin-1-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona cloridrato de l-(4-etano-sulfonil-2,5-difluoro-fenil)- piperazina (composto 6.33) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 602,3 (M+NH/) 616 rac-[4-(4-ciclopropano-sulfonil-2,5-difluoro-fenil) -piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona cloridrato de 1-(4-ciclopropano-sulfonil-2,5-difluoro-fenil)-piperazina (composto 6.34) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 614,3 (M+NH4+) 617 ' [4-(4-hidroxi-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona 4-piperazin-l-il-fenol (comercial) ê ácido 2-isopropoxi-5-metang-sulfonil-benzóico (composto 1.2) 419,1 618 rac-(2-isopropoxi-5-metano-sulfonil-fenil)-[3-metil-4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona cloridrato de rac-2-metil-l-(4-trifluorometil-fenil)-piperazina (composto 6.35) e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 485,2 619 1-{4-isopropoxi-3-[4—(4— trifluorometil-fenil)-piperazino-l-carbonil]- 1-(4-trifluorometil-fenil)-piperazina (comercial) e ácido 5-acetil-2-isopropoxi-benzóico 435,2 185 fenil}-etanona (composto 6.36)Exemp. Systematic Name Initial Materials PM found. Methyl 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-ethoxy-benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-ethoxy-5-sulfamoyl-benzoic acid (JP 53050139) 433.2 473 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine- carbonyl] -4-ethoxy-benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-ethoxy-5-sulfamoyl-benzoic acid (JP 53050139) 3 (MH) 474 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-ethoxy-benzenesulfonamide 4-piperazin-1-yl-butyzonitrile (commercial) and 2-ethoxy- 5-sulfamoylbenzoic acid (JP 53050139) 413.3 (MH) 475 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-isobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.1) 475.1476 3- [4- (4- -cyano-3-fluoro-phenyl) -piperazine-1-carbon (2-fluoro-4-piperazin-1-yl) -benzonitrile (WO 9808835) and 2- (2,6-dichlorophenyl) Dimethylpropoxy) -5-methylsulfamoylbenzoic acid (compound 6.2) 489.3477 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy- 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-isopropoxymethylsulfamoyl benzoic acid (compound 6.3) 461.2 478 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile WO 9428035) and 2-cyclopentyloxy-5-methylsulfamoylbenzoic acid 487.3 168 (compound 6.4) 479 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-cyclobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.5) 480 3- [4- (4-cyano-3-fluoro 1-carbonyl] -4-cyclopropylmethoxy-N-methyl-benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-cyclopropylmethoxy-5- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl) -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide 2-fluoro- 4-piperazin-1-yl-benzonitrile (WO 9808835) and 2-cyclobutylmethoxy-5-methylsulfamoylbenzoic acid (compound 6.7) 487.3 482 3- [4- (4-cyano-3-fluoro-phenyl ) -piperazine-1-carbonyl] -N-methyl-4- (tetrahydro-pyran-4-yloxy) -benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-ethylsulfamoyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound 6.8) 503.2 483 3- [4- (4-cyano-3-fluoro-phenyl) -piperazin- carbonyl] -4- (2-methoxy-ethoxy) -N-methyl-benzenesulfonamide 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 2- (2-methoxyethoxy ) -5-methylsulfamoyl-benz (compound 6.9) 477.3 484 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (3,3,3-trifluoro-propoxy) 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methylsulfamoyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid. (compound 6.10) 515.2 485 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4- (2-methoxy-ethoxy) -N-methyl-benzenesulfonamide 4-piperazin-1 -benzonitrile (commercial) and 2- (2-methoxy-ethoxy) -5-methylsulfamoyl-benzoic acid (compound 6.9) 459.1. 486 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide 4-piperazin- benzonitrile (commercial) and 5-methylsulfamoyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 6.10) 497.0 169 487 3- [4- (4-cyanophenyl) 1-carbonyl) -N-methyl-4- (tetrahydro-pyran-4-yloxy) -benzenesulfonamide 4-piperazin-1-yl-benzonitrile (commercial) and 5-methylsulfamoyl-2- (tetrahydro- 4-yloxy) benzoic acid (compound 6.8) 485.2 488 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide 4- piperazin-1-yl-benzonitrile (commercial) and 2-isobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.1) 457.3 489 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] - 4- (2,2-dimethyl-propoxy) -N-methyl-benzenesulfonamide 4-piperazin-1-yl-benzonitrile (commercial) and 2- (2,2-dimethyl-propoxy) -5-methylsulfamoyl- benzoic acid (compound 6.2) 471.1 490 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-N-methyl-benzenesulfonamide amide 4-piperazin-1-yl-benzonitrile (commercial) and 2-isopropoxy-5-methylsulfamoyl-benzoic acid (compound 6.3) 443.2 491 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl ] -4-cyclopentyloxy-N-methylbenzenesulfonamide 4-piperazin-1-yl-benzonitrile (commercial) and 2-cyclopentyloxy-methylsulfamoyl-benzoic acid (compound 6.4) 469.2 492 3- [4- (4- phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide 4-piperazin-1-yl-benzonitrile (commercial) and 2-cyclobutoxy-5-ethylsulfamoyl-benzoic acid (compound 6.5) 3 493 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-cyclopropylmethoxy-N-methyl-benzenesulfonamide 4-piperazin-1-yl-benzonitrile (commercial) and 2-cyclopropylmethoxy acid -5-methylsulfamoylbenzoic acid (compound 6.6) 455.3494 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide 4-piperazin-1 -yl-benzonitrile (commercial). and 2-cyclobutylmethoxy-5-methylsulfamoylbenzoic acid (compound 6.7) 469.2495 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-isobut (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-isobutyl-5-methylsulfamoyl-benzoic acid (compound 6.1) . 496 4- (2,2-dimethyl-propoxy) -3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl) -N-methyl-1- (2-fluoro- 4-methanesulfonyl-phenyl) -piperazine (commercial) and 2- (2,2-dimethyl-propoxy) -5-methylsulfamoyl-benzoic acid 559.2 (M + NH /) 170 benzenesulfonamide (compound 6.2) 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-isopropoxy-5-methylsulfamoyl-benzoic acid (compound 6.3) 514.1 4 93 4-cyclopentyloxy-3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine- 1-carbonyl] -N-methyl-benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) 4-cyclobutoxy-3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carboxylic acid (Compound 6.4) carbonyl] -N-methyl-benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-cyclobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.5) 526.0 500 3- (4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -N-methyl-benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl- 2-cyclopropylmethoxy-5-ethylsulfamoyl-benzoic acid (compound 6.6) 526.0 501 4-cyclobutylmethoxy-3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1 -carbony] -N-methyl-benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-cyclobutylmethoxy-5-methylsulfamoyl-benzoic acid (compound 6.7) 557.0 ( M + NH 4 +) 502 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4- (2-methoxy-ethoxy) -N-methyl-benzenesulfonamide - (2-fluoro-4-methanesulfonyl-phenyl) -piperaz 2- (2-methoxy-ethoxy) -5-methylsulfamoyl-benzoic acid (compound 6.9) 530.1 503 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) - piperazine-1-carbonyl] -N-methyl-4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-methylsulfamoyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 6.10) 585.0 (M + NH4 +) 504 3- [4- (4-cyano-2-fluoro-phenyl) - piperazin-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-isobutoxy- methylsulfamoylbenzoic acid (compound 6.1) 475.0 505 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2,2-methyl-propoxy) -N-methyl 3-fluoro-4-piperazin-1-yl-. (4,2-dimethyl-propoxy) -5- [4- (4-cyano-2-methylphenyl) benzoic acid methyl ester sulfonamide (compound 6.2) fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-N-methyl-benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-isopropoxy- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzoic acid (Compound 6.3) benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (compound 6.4) 487.1 508 3- [4- 2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-methyl-benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and cyclobutoxy- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopropylmethoxy-N-methyl-benzenesulfonic acid 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-cyclopropylmethoxy-5-methylsulfamoyl-benzoic acid (compound 6.6) .472.8 510 3- (4- -2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-ethyl-benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2- cyclobutylmethoxy-5-methylsulfinoyl benzoic acid (compound 6.7) 487.1 511 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (tetrahydro- 4-yloxy) -benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-ethylsulfamoyl-2- (tetrahydro-5-pyran-4 (compound 6.8) 503.0 512 3- [4- (4-Amino-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2-methoxy-ethoxy) -N-methyl 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2- (2-methoxy-ethoxy) -5-methylsulfamoyl-benzoic acid (compound 6.9) 477.1 513 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine 1-carbonyl] -N-methyl-4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-methylsulfamoyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid 515.1172 (compound 6.10) 514 3- [4- (4-acetyl-2-fluoro- piperazin-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2-isobutoxy- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2,2-dimethyl-propoxy) -N- methyl-benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2- (2,2-dimethyl-propoxy) -5-methylsulfamoyl- (4-acetyl-2-fluorophenyl) piperazine-1-carbonyl] -4-isopropoxy-N-methylbenzenesulfonamide 1- (3- fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2-oxopropoxy-5-methylsulfamoyl-benz (compound 6.3) 478.2 517 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl) -4-cyclopentyloxy-N-methyl-benzenesulfonamide 1- (3-fluoro 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (compound 6.4) 504.2 518 3- [4- (4-acetyl-2-propylamino) -4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) 1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2-cyclobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.5) 590, 6199 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazino-1-carbonyl] -4-cyclopropylmethoxy-N-methyl -benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone (WO 9714690) and 2-cyclopropylmethoxy-5-methylsulfamoyl-benzoic acid (compound 6.6). 490.2 520 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzenesulfonamide 1- (3-fluoro-4-piperazin-1 -phenyl) -ethanone (WO 9714690) and 2-cyclobutylmethoxy-5-methylsulfamoylbenzoic acid (compound 6.7) 504.2 521 3- [4- (4-acetyl-2-fluoro-phenyl) ) -piperazine-1-carbonyl] -N-methyl-4- (tetrahydro-pyran-4-yloxy) -benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) - ethanone (WO 9714690) and 5-methylsulphthioyl-2- (tetrahydro-pyran-4-yloxy) -benzoic acid (compound.6.8) 520.3 173 522 3- [4- (4-acetyl-2- 1-carbonyl] -4- (2-methoxy-ethoxy) -N-methyl-benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethano- WO 9714690) and 2- (2-methoxyethoxy) -thiazolylsulfamoyl-benzoic acid (compound 6.9) 494.2 523 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1 -carbonyl] -N-methyl-4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethane 5-methylsulfamoyl-2- (3,3,3-trifluoro-propoxy) -benzoic acid (compound 6.10) 532.2 524 4-isobutoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-isobutoxy-5-methylsulfamoyl-benzoic acid (compound 6.1) 525 4- (2,2-dimethyl- {4- (4-trifluoromethyl- [4- (4-trifluoromethyl-phenyl) -piperazin-1] -carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl-phenyl) - piperazine (commercial) and 2- (2,2-dimethyl-propoxy) -5-methylsulfamoyl-benzoic acid (compound 6.2) 514.2 526 4-isopropoxy-N-methyl-3- [4- (4-trifluoromethyl -phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) is 2-isopropoxy-5-methylsulfamoyl-benzoic acid (compound 6.3) 486.2 527 3- (4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclopentyl- (compound 6.4) 512.3 528 4-Cyclobutoxy-N-ethyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1-methyl- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclobutoxy-5-methylsulfamoyl-benzoic acid (Compound. 5.5) 498.2 529 4-cyclopropylmethoxy-N-ethyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl-phenyl) -piperazine ) and 2-cyclopropylmethoxy-5-methylsulfamoyl-benzoic acid (compound 6.6) 498.2 530 4-cyclobutylmethoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzene- sulfonamide 1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 2-cyclobutylmethoxy-5-methylsulfamoyl-benzoic acid (compound 6.7) 512.3 531 N-methyl-3- [4- (4- 4-trifluoromethyl-phenyl) -540,2-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide piperazine (commercial) and 5-ethylsulfamoyl -3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl- 2-fluoro-4-piperazin-1-yl-benzonitrile (WO 9808835) and 5-methylsulfamoyl-2-fluoro-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide. (2,2,2-trifluoro-ethoxy) -benzoic acid (c (6.11) 501.1 533 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide 4-piperazin 5-methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 6.11) 483.3 534 3- [4- (4-cyano-2- fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide 3-fluoro-4-piperazin-1-yl-benzonitrile (Patent of Invention WO 9625414) and 5-methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 6.11) 501, 1355 3- [4- (4-acetyl-2-fluoro-phenyl) - piperazino-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide 1- (3-fluoro-4-piperazin-1-yl-phenyl) -ethanone WO 9714690) and 5-methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 6.11) 518.2 536 3- [4- (2-fluoro-4-methanesulfonyl-phenyl ) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and acid of 5-methylsulfamoyl-2- (2,2,2-trifluoroethoxy) benzoic acid. (compound 6.11) 554.1 537 N-Methyl-4- (2,2,2-trifluoro-ethoxy) -3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1 - (4-trifluoromethyl-phenyl) -piperazine (commercial) and acid. 5-ethylsulfamoyl-2- (2,2,2-trifluoro-ethoxy) benzoic acid (compound 6.11) 526.0 538 [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (2-isopropoxy-5-methanesulfonyl- (compound 1.2) 513.3 175 539 {4- [4- (butane-1-sulfonyl) -2-fluoro-2-isopropoxy-5-methanesulfonyl-phenyl}} - methanone 1- [4- 1-sulfonyl) -2-fluoro-phenyl] -piperazine (compound 6.13) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 541.0 540 4- [4- (5-cyclopropane 2-isopropoxy-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-cyclopropane 2-isopropoxy-benzoic acid (compound 6.14) 472.3 541 (5-cyclopropanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -ethanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and 5-cyclopropyl- -2-isopropoxy-benzoic acid (compound 6.14) 515.4 542 (5-cyclopropanesulfonyl-2-isobutoxy-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-cyclopropanesulfonyl-2-isobutoxy-benzoic acid (compound 6.15) 539.5 543 4- [4- (5-cyclopropanesulfonyl-2-isobutoxybenzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-cyclopropanesulphonyl-2-isobutyloxy-benzoic acid (compound 6.15) 486.5 544 (5-cyclopropanesulphonyl-2-isobutoxy-phenyl) - [4- (2-fluoro-4- trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and 5-cyclopropanesulfonyl-2-isobutoxy-benzoic acid (compound .. 6.15) (2-cyclopentyloxy-5-cyclopropane-sulfonyl-phenyl) - [4 '- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-cyclopentyloxy-5-cyclopropanesulfonylbenzoic acid (compound 6.16) 551.3 546 4- [4- (2-cyclopentyloxy-5-cyclopropanesulfonylbenzoyl) -piperazin-1-yl] - 3-fluoro-benzoyl nitrile 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 2-cyclopentyloxy-5-cyclopropanesulfonyl-benzoic acid (compound 498.3 176 6.16) cyclopentyl-5-cyclopropanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl-phenyl) -piperazine (compound 1.1) and 2-cyclopentyloxy-5-cyclopropanesulfonylbenzoic acid (compound 6.16) 541.3 543 (5-cyclopropanesulfonyl-2-cyclopropylmethoxy-phenyl) - [4- (2-fluoro-4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 5-cyclopropanesulfonyl-2-cyclopropylmethoxy-benzoic acid (compound 6.17) 537.4, 549 4- [4- (5-cyclopropane-sulfonyl-2-cyclopropylmethoxy-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile. 3-fluoro-4-piperazin-1-yl-benzonitrile (WO 9625414) and 5-cyclopropanesulfonyl-2-cyclopropylmethoxy-benzoic acid (compound 6.17). 484.5 550 (5-Cyclopropanesulfonyl-2-cyclopropylmethoxy-phenyl) - [4- (2-fluoro-4-trifluoromethylphenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-trifluoromethyl 5-cyclopropanesulfonyl-phenyl) - (4- (2-cyclobutoxy) -5-cyclopropanesulfonyl-2-cyclopropylmethoxy-benzoic acid (compound 6.17) fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-cyclobutoxy-5-cyclopropanesulfonyl (compound 6.18) 537.4 552 (5-cyclopropanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone (Commercial) and 5-cyclopropanesulfonyl-2-isopropoxy-benzoic acid (compound 6-14) 525.3 553 rac-3- [Î ± -cyclohexanecarboxylic acid] 4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazino-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and rac-5-methylsulfamoyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 6.19) 585.1 (M + NH /) rac-N-methyl- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide 1- (4-trifluoromethyl- phenyl) -piperazine (commercial) and rac-5-methylsulfamoyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound. 6.19) 557.2 (Κ + ΝΗ 4 +) 555 rac-3- [4- (4-cyano-2-fluoro-3-fluoro-4-piperazin-1-yl-53,2,3,17indenyl) piperazin- carbonyl] -N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide benzonitrile (WO 9625414) and rac-5-methylsulfamoyl-2- , 4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -piperazine-2-carboxylic acid (Compound 6.19) (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 542.2 (M + NH 4 +) 557 rac-3- [4- (4-cyano-2,5-difluoro-phenyl) -piperazine-1-carbonyl] -N-methyl- 2,5-difluoro-4-piperazin-1-yl-benzonitrile-trifluoroacetic acid (compound 2.8) and rac-5-methylsulfamoyl-2-oxo-2,2-trifluoromethyl- (4-cyano-2,3-difluoro-phenyl) -piperidine-5-carboxylic acid (Compound 6.19) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide 2,3-difluoro-4-piperazin-1-yl-benzoyltriyl-trifluoroacetic acid (compound 2.7) and rac (M + H +) 559 {4- (2-Fluoro-4-propane-2-carboxylic acid [2- (2,2,2-trifluoro-1-methyl-ethoxy) sulfonyl) -phenyl] -piperazin-1-yl} - (2-isopropoxy-5-methanesulfonyl-phenyl} -methanone 1- [2-fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.21) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 544.3 (M + NH 4). 560 [4- (4-cyclopropylmethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl- -phenyl) -methanone 1- (4-cyclopropylmethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.22) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 556.2 '. (M + NH 4 + ') 561 {4- [2-fluoro-4- (2-methoxy-ethanesulfonyl) -phenyl] -. piperazin-1-yl} - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- [2-fluoro-4- (2-methoxy-ethanesulfonyl) -phenyl] -piperazine (compound 6.23) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound, 1.2) 5 60.3 (M + NH) 562 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-ethano- sulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and 2-cyclopropylmethoxy-5-methanesulfonyl- benzoic acid methyl ester (compound 1.4) 542.2 (M + NH4 +) 563 (2-cyclopentyloxy-5-methanesulfonyl-pentyl) - [4- (4-4- [1- (4-ethanesulfonyl- fluoro-phenyl) -piperazine (compound 556.1 (M + NH4 +)) and 2-cyclopentyloxy-5-methanesulfonyl-2-fluoro-phenyl) -piperazin- benzoic acid (compound 1.6) .564, (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1 - (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid; (compound 3.2) 570.2. (M + NH +) 565 [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin- yl) -methanone 1- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and 2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 558.2 (M + NH 4 +) 566 [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone 2-fluoro-phenyl) -piperazine (compound 6.12) and 2-isobutoxy-5-methanesulfonyl-benzoic acid (compound 1.3) 544.2 (M + NH 4 +) (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1- (4-ethanesulfonyl- -2-fluoro-phenyl) -piperazine (compound 6.12) and 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 542.3 (M + NH /) 568 rac- (2-sec-butoxy-5- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and rac-2-sec-butyl-5-methyl benzoic acid (compound 3.5) 544.2 (M + NH 4 +). 569 (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1- (4-ethanesulfonyl-2- fluoro-phenyl) -piperazine (compound 6.12) and 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (compound 2.12). 556.1 (M + NH 4 +) 570 [4- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone hydrochloride 1- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.24) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 556.1 (M + NH4 +). 5- (4-cyclopentanesulfonyl-2-fluoro-phenyl) -piperazine-1- (4-cyclopentanesulfonyl-2-fluoro-phenyl) -570.3 (M + NH4 +) 1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone piperazine (compound 6.25) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 572 [4- (4-cyclopropanesulfonyl- fluoro-phenyl) -piperazin-1-yl] - (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) - piperazin-1-yl] -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 568.0 ( M + NH 4 +) 574 (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone 1- (4 -cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-cyclohexyloxy-5-methanesulfonylbenzoic acid (compound 3.2) 582.1 (M + NH /) 575 [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) 1-yl] - [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2- (2,2-dimethylpropoxy) -5-methanesulfonyl-benzoic acid (compound 3.3) 570.2 (M + NH 4 +) 576 (2-cyclobutoxy-5-methanesulfonyl- phenyl) -piperazin-1-yl] -methanone 1- (4-cyclopropane-sulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (compound 3.4) 536.9 577 (4- (2-fluoro-4- (3,3,3-trifluoropropane-1-sulphonyl ) -phenyl] -piperazin-1-yl} - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- [2-fluoro-4- (3,3,3-trifluoro-propion- sulfonic acid) -phenyl] -piperazine (compound 6.26) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 581.0 578 [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl ) -piperazin-1- yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 2-isobutoxy- (4-sulfonyl) benzoic acid (compound 1.3) 556.1 (M + NH4 +) 579 {4- (2-fluoro-4- (tetrahydro-pyran-4-sulfonyl) -phenyl] -piperazin-1-yl} - ( 2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (2-fluoro-4- (tetrahydro-pyran-4-sulfonyl) -phenyl] -piperazine (compound 6.27) and 2-isopropoxy- (2-fluoro-4-methanesulfonyl-phenyl) -methanesulfonyl-benzoic acid (compound 1.2) 586.2 (M + NH4 +) 580 (2-tert-butoxy- - (propane-2-sulfonyl) -phenyl] -piperazine 558.2 (M + NH 4 +) 180 fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazin-1-yl} -methanone (compound 6.21) and 2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluorophenyl) -2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2.19) 1-yl] -methanone 1- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.12) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2.19) 544.2 (M + NH) 582 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - methanone 1- (4-cyclopropanesulfonyl-2-fluorophenyl) piperazine (compound 6.20) and 2-tert-butoxy-5-methanesulfonylbenzoic acid (compound 2.19) 556.1 (M + NH /) 583 4- [2-fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazin-1-yl} - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] 1- [2-fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.21) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 584.1 <M + NH4 +) 584 [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy ) -phenyl] -methanone 1- (4-ethanesulfonyl-2-fluorophenyl) -piperazine (compound 6.12) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 570.3 (M + NH /) 585 [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl- 2-trifluoro-ethoxy) -phenyl] -methanone 1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.20) and 5-methanesulfonyl-2- (2,2,2- -ethoxy) -benzoic acid (compound 1.5) 582.1 (M + NH4 +) 586 rac- {4- [2-fluoro-4- (propane-2-sulfonyl) - [5-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- [2-fluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.21) and rac- 2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 598.2 (M + NH4 +) 587 rac- [4- (4-ethanesulfonyl-2-fluoro- phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methane 1- (4-phenyl) -2-fluoro-phenyl) -piperazine (compound 6.12) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 584.1 (M + NH) 588 rac- [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -1- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazine (Compound 596.2 (M + NH4 +)) was added piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] ) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 589 [4- (4-cyclohexane- sulfonyl-2-fluoro-phenyl} -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- (4-cyclohexanesulfonyl-2-fluoro-phenyl) -piperazine (compound 6.28) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 584.3 (M + N 10 590 {4- [2,3-difluoro-4- (propane-2-sulfonyl) ) -piperazin-1-yl} - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- [2,3-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine hydrochloride ( Compound 6.29) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 545.2 591 [4- (4-ethanesulfonyl-2,3-difluoro-phenyl) -piperazin-1-yl] - 1- (4-ethanesulfonyl-2,3-difluoro-phenyl) -piperazine (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone hydrochloride (compound 6.30) and 2- isopropoxy-5-methanesulfonylbenzoic acid (compound 1.2) 531.1 592 (4- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5- methanesulfonyl-phenyl) -methanone 1- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazine hydrochloride (compound 6.31) and 2-iso propoxy-5-methanesulfonylbenzoic acid (compound 1.2) 543.3 593 {4- [2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazin-1-yl) - (2- isopropoxy-5-methanesulfonyl-phenyl) -methanone 1- [2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine hydrochloride (Compound 6.32) and 2-isopropoxy-5- (4-ethanesulfonyl-2,5-difluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methyl- 1- (4-phenyl) -2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.33) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2 ) 531.1. 595 [4- (4-cyclopropanesulfonyl-2,5-difluoro-phenyl) -piperazin-1-yl] - (2-isopropaxy-5-methanesulfonyl-phenyl) -methanone hydrochloride 1- (4-cyclopropane hydrochloride (compound 6.34) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 543.3 596 (2-tert-butoxy-5-methylsulfonyl-2,5-difluoro- methanesulfonyl-phenyl) - [4- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone. (compound 2.19) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2.19) 553.6 597 (compound 1- [2,3-Difluoro-4-oxo-2-sulfonyl] -2- (4- (2,3-difluoro-4- (propane-2-sulfonyl) ) -phenyl] -piperazin-1-yl) -methanone (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.29) and 2-tert-butoxy-5-methanesulfonyl-benzoic acid (compound 2.19) (M-tBu + H) 598 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2,3-difluoro-phenyl) -piperazin-1-yl] 1- (4-ethanesulfonyl-2,3-difluorophenyl) piperazine hydrochloride (compound 6.30) and 2-tert-butoxy-5-methanesulfonyl- (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) ) -methanone hydrochloride (compound 6.31) and 2-tert-butoxy-5- (4-cyclopropylsulfonyl-2,3-difluoro-phenyl) -piperazine hydrochloride methanesulfonyl-be (2-tert-butoxy-5-methanesulfonyl-phenyl) - (4- [2,5-difluoro-4- (propane-2-sulfonyl) ) -phenyl] -piperazin-1-yl} -methanone 1- [2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine hydrochloride (compound 6.32) and 2- tert -butoxy- 5-methanesulfonyl-benzoic acid (compound 2.19) 503.2 (M-tBu + H) 601 (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl- 2,5-difluoro-phenyl) -piperazin-1-yl] -methanone 1- (4-ethanesulfonyl-2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.33) and 2- butoxy-5-methanesulfonamide. (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2,5-difluoro- -phenyl) -piperazin-1-yl] -methanone 1- (4-cyclopropanesulfonyl-2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.34) and 2-tert-butoxy-5-methanesulfonyl- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2-methyl- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazine hydrochloride (compound 6.24) and 5-methanesulfonyl- 2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 579.1604 (4- [2,3-Difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazin-1- yl} - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -hydrochloride of 1- [2,3-difluoro-4- (propane-2-sulfonyl) -phenyl] ] -piperazine (compound 6; 29) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid 602.2 (M + NH4 +) 183 methanone (compound 1.5) - (4-ethanesulfonyl-2,3-difluoro-phen yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone 1- (4-ethanesulfonyl- 3-difluoro-phenyl) -piperazine (compound 6.30) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 571.2 606 [4- (4-cyclopropane (5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone hydrochloride hydrochloride 1- (4-methoxyphenyl) -piperazin-1-yl] -cyclopropane-sulfonyl-2,3-difluoro-phenyl) -piperazine (compound 6.31) e. 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 600.2 (M + NH4 +) 607 (4- [2,5-difluoro-4- 2-sulfonyl) -phenyl] -piperazin-1-yl} - [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] -methanone hydrochloride 1- [2,5- difluoro-4 (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.32) and 5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -benzoic acid (compound 1.5) 602.3 (M + NH 4 +) 608 [4- (4-ethanesulfonyl-2,5-difluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- ethoxy) -phenyl] -methanone 1- (4-ethanesulfonyl-2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.33) and 5-methanesulfonyl-2- (2,2,2- trifluoro-ethoxy) -benzoic acid (compound 1.5) 588.3. (M + NH) 609 [4- (4-cyclopropanesulfonyl-2,5-difluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro 1- (4-cyclopropanesulfonyl-2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.34) and 5-methanesulfonyl-2- (2,2,2- (4-fluoro-2-fluoro-phenyl) -piperazin-1-yl] - [5- (trifluoromethoxy) 1- (4-cyclobutane-2-sulfonyl-2-fluoro-phenyl) -piperazine hydrochloride (compound 6.24) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3.1) rac- {4- [2,3-difluoro- (propane-2-sulfonyl) -phenyl] -piperazin-1-yl} - [5-methanesulfonyl-2- (2,2,2- 2-sulfonyl) -phenyl) -piperazine (compound 6.29) and rac-5-methanesulfonyl-2- (trifluoro-1-methyl-ethoxy) -phenyl] -methanone (2,2,2-trifluoro -1-methyl-ethoxy) -benzoic acid (compound 3.1) 612 rac- [4- (4-ethane sulfonyl-2,3-difluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone hydrochloride 1- (4-ethanesulfonyl-2,3-difluorophenyl) piperazine (compound 6.30) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 602.2 (M + NHa +) 613 rac- [4- (4-cyclopropanesulfonyl-difluoro-phenyl) -6.31) and piperazin-1-yl] - [5-methanesulfonyl] 2,3-1- (4-cyclopropanesulfonyl-2,3-difluoro-phenyl) -piperazine-2 (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone hydrochloride 6.31) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 614.3 (M + 2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazin-1-yl} - {5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone hydrochloride of 1- [2,5-difluoro-4- (propane-2-sulfonyl) -phenyl] -piperazine (compound 6.32) and rac-5-methanesulfonyl- 2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 616.2. (M + NH) 615 rac- [4- (4-ethanesulfonyl-2,5-difluoro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- (4-methanesulfonyl-2,5-difluoro-phenyl) -piperazine hydrochloride (compound 6.33) and rac-5-methanesulfonyl-2 - (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (Compound 3.1) 602.3 (M + NH /) 616 rac- [4- (4-cyclopropanesulfonyl-2,5-difluoro- phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone hydrochloride 1- (4-cyclopropanesulfonyl- 2,5-difluoro-phenyl) -piperazine (compound 6.34) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) 614.3 (4-hydroxy-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone 4-piperazin-1-yl-phenol (M + NH4 +) commercial) is 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) 419.1 618 rac- (2-isopropoxy-5-methanesulfonyl-phenyl) - [3-methyl-4- (4-trifluoromethyl -phenyl) -piperazin-1-yl] -methanone rac-2-methyl-1 2-isopropoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine (compound 6.35) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) trifluoromethyl-phenyl) -piperazine-1-carbonyl] -1- (4-trifluoromethyl-phenyl) -piperazine (commercial) and 5-acetyl-2-isopropoxy-benzoic acid 435.2, 185phenyl} -ethanone (compound 6.36)

Exemplo 6.37Example 6.37

Preparação do ácido 4-isopropoxi-3-[4-{4-tri£luorometil-fen.il) -piperazino-l-carbonil] -benzóico (a) 4-Isopropoxi-3-[4-(4-trifluorometil-fenil)-piperazino-1-carbonil-benzonitrilo A uma solução de 3,6 mmole do áçido 5-ciano-2-isopropoxi-benzóico (composto 1.13), no seio de 20 mL de THF, adicionou-se 4,0 mmole de TBTU, 21,6 mmole de N-etildi-isopropilamina e 4,0 mmole de 1-(4-trifluorometil-fenil)-piperazina (comercial). -Agitou-se então a mistura reaccional à TA, durante 16 horas, concentrou-se in vacuo e purificou-se por cromatografia em gel de sílica (eluente: acetato de etilo/heptano a 1:1), para se obter o composto do título. EM (m/e): 418,3 (M+H+, 100 %) (b) Ácido 4-isopropoxi-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil] -benzóico A 3,2‘ mmole de ' 4-ísópropoxi-3- [-4-(4-trifluorometil-fenil) -piperazino-l-carbonil]-benzonitrilo, . no seio .de 15 mL de etanol, adicionou-se 30 mmole de NaOH aquoso 2 M.e aqueceu-se a mistura a 85 °C, durante. 16 horas. Arrefeceu-se então a mistura para a TA, diluiu-se. com água e acidificou-se para pH de 1 com HC1 concentrado e depois extraiu-se 3 vezes com acetato de. etilo. Secaram-se as fases orgânicas combinadas com Na2S04, concentrou-se in vacuo e purificou-se o resíduo por cromatografia em gel de sílica (eluente: metanol/diclorometano a 5:95), para se obter o composto do título. EM (m/e): 435,3 (. [Μ—H] ”, 100 %) 186Preparation of 4-Isopropoxy-3- [4- (4-trifluoromethylphenyl) -piperazine-1-carbonyl] -benzoic acid (a) 4-Isopropoxy-3- [4- (4-trifluoromethyl-phenyl ) -piperazine-1-carbonyl-benzonitrile To a solution of 3.6 mmole of 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 mL of THF was added 4.0 mmol of TBTU , 21.6 mmol of N-ethyldiisopropylamine and 4.0 mmol of 1- (4-trifluoromethyl-phenyl) -piperazine (commercial). The reaction was then stirred at RT for 16 hours, concentrated in vacuo and purified by silica gel chromatography (eluent: ethyl acetate / heptane 1: 1) to give the title compound. title. (B) 4-Isopropoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzoic acid To a solution of 3- 4-Isopropoxy-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzonitrile, m.p. in 15 ml of ethanol was added 30 mmole of 2 M aqueous NaOH and the mixture was heated at 85 ° C for 2 hours. 16 hours. The mixture was then cooled to RT, diluted. with water and acidified to pH 1 with concentrated HCl and then extracted 3 times with ethyl acetate. ethyl. The combined organic phases were dried over Na2SO4, concentrated in vacuo and the residue purified by silica gel chromatography (eluent: 5:95 methanol / dichloromethane) to give the title compound. MS (m / e): 435.3 (M + H) +, 100%) 186

Exemplo 620Example 620

Preparação do éster metálico do ácido 4-isopropoxi-3-[4-4-trifluoroittetil-fenil)-piperazino-l-carbonil]-benzóico A 0,3 mmole do ácido 4-isopropoxi-3-[4-(4-trifluoro-metil-fenil)-piperazino-l-carbonil]-benzóico, no seiõ de 2 mL de. DMF, adici.onou-se 0,4 mmole de CDI e aqueceu-se a mistura a 50 °C, durante 30 minutos. Adicionou-se então 5,2 mmole de metanol, e agitou-se- a mistura à TA, durante 16 horas. Arrefeceu-se então a' mistura para a temperatura ambiente, concentrou-se in vacuo e purificou-se o resíduo por cromatografia em gel. de sílica (eluente: acetato de etilo/heptano a 1:4), para se obter o composto do titulo. EM (m/e): 451,2 (M+H+, 100 %)Preparation of 4-isopropoxy-3- [4- (4-trifluoromethoxy-phenyl) -piperazine-1-carbonyl] -benzoic acid methyl ester To 0.3 mmole of 4-isopropoxy-3- [4- (4-trifluoro methyl-phenyl) -piperazine-1-carbonyl] -benzoic acid, in the form of 2 ml. DMF, 0.4 mmol of CDI was added and the mixture was heated at 50 ° C for 30 minutes. 5.2 mmol of methanol was then added, and the mixture was stirred at RT for 16 hours. The mixture was then cooled to room temperature, concentrated in vacuo and the residue was purified by gel chromatography. of silica (eluent: ethyl acetate / heptane 1: 4) to give the title compound. MS (m / e): 451.2 (M + H +, 100%)

Exemplo 621Example 621

Preparação de 4-isopropoxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazino-l-carbonil]-benzamida A 0,3 mmole do ácido 4-isopropoxi-3-[4-(4-trifluoro-metil-fenií)-piperazino-l-carbonil]-benzóico, no seio de 2 mL de DMF, adicionou-se 0,4 mmole de CDI e aqueceu-se a mistura a 50 °C, durante 30 minutos. Adicionou-se então 5,2 mmole de metilamina (solução aquosa a 41 %) e agitou-se a mistura à TA, durante 16 horas. Arrefeceu-se então a mistura para a temperatura ambiente, concentrou-se in vacuo e purificou-se o resíduo por cromatografia em gel de sílica (eluente: acetato de etilo), para se obter o composto do título. EM (m/e): 450,1 (M+H+, 100 %)Preparation of 4-isopropoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzamide To 0.3 mmol of 4-isopropoxy-3- [4- (4- trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzoic acid in 2 mL of DMF was added 0.4 mmol of CDI and the mixture was heated at 50 ° C for 30 minutes. 5.2 mmol of methylamine (41% aqueous solution) was then added and the mixture was stirred at RT for 16 hours. The mixture was then cooled to room temperature, concentrated in vacuo and the residue purified by silica gel chromatography (eluent: ethyl acetate) to provide the title compound. MS (m / e): 450.1 (M + H +, 100%)

Exemplo 6.38 187 &lt;r»Example 6.38 187 <r »

Preparação de 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil] -4-hidroxi-benzeno-siilfonainida (a) Ácido 2-hidroxi-5&quot;Sulfamoil-benzóicoPreparation of 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (a) 2-Hydroxy-5 &quot; Sulfamoyl-benzoic acid

Fez-se borbulhar amónia gasosa através de uma solução de 107 mmole do ácido 5-cloro-sulfoni'l-2-hidroxibenzóico, no seio de 250 mL de acetona, a 0 °C, durante 2 horas. Depois . fez-se borbulhar árgon gasoso através da mistura reaccional, durante 1 hora, para purgar o excesso de amónia. Diluiu-se então a mistura com água, ajustou-se o pH para 14 por adição .de uma solução de NaOH aquosa 5 M e depois extraiu-se a mistura com éter/acetato de etilo (1:1).· Acidificou-se a fase aquosa com HC1 concentrado, saturou-se com NaCl e extraiu-se duas- vezes com THF. Secaram-se os extractos combinados de THF com Na2SC&gt;4. A evaporação do dissolvente in vacuo seguida da secagem do resíduo por aquecimento a 60 °C, durante a noite, ín vacuo, originou o composto do título. EM (m/e): 216,1 ([M-H]“, 100 %) (b) Éster metílico do ácido 2-hidroxi-5-sulfamoil-benzóico A 62 mmole do ácido 2-hidroxi-5-sulfamoil-benzóico, no seio de 80 mL de THF, adicionou-se 80 . mmole de CDI e aqueceu-se a mistura a 50 °C, durante 1 hora. Adicionou-se então 616 mmole de metanol e aqueceu-se a mistura a 50 °G, durante 16 horas. Arrefeceu-se então a mistura para a temperatura ambiente, conc'entrou-se in vacuo e purificou-se o resíduo por cromatografia em gel de sílica (eluente: dicloro-metano/metanol a 20:1). Concentrou-se o produto contendo as fracções in vacuo e suspendeu-se o resíduo no seio de acetato de etilo e lavou-se com uma solução de NaHC03 aquosa.' Secou-se a fase orgânica com Na2S04 e 188 concentrou-se in vácuo, para se- obter o composto do titulo. EM (m/e) : 230,2 ([M-H]&quot;, 100 %), ' (c) Éster metílico do ácido 2-(4-metoxi-benziloxi)-5-sulfamoil-benzóico A 4,8 mmole do éster metílico do ácido 2-hidroxi-5-sulfamoil-benzóico, 5,2 mmole do álcool 4-metoxibenzíliço e 5,2 mmole de trifenilfosfina, no seio de 8 mL THF, adicionou-se 5,2 mmole de azodicarboxilato de di-terc-butilo e agitou-se a mistura à TA, durante 2 horas. Concentrou-se então a mistura in vacuo. Fez-se a cromatografia do resíduo em gel de sílica (eluente: gradiente de acetato de etilo/heptano), para se obter o composto do título. EM (m/e): 350,2 ([M-H]”, 100 %) (d) Ácido 2-(4-metoxi-benziloxi)-5-sulfamoil-benzóico A 2,5 mmole do éster metílico do ácido 2-(4-metoxi-benziloxi) -5-sulfamoil-benzóico, no seio de 6 mL de THF, adicionou-se 5 mmole de NaOH aquoso 2 M e aqueceu-se a mistura a, 60 °C, durante 30 minutos. Arrefeceu-se então a mistura para a. TA e extraiu-se duas vezes com acetato de 'etilo. Acidificou-se a fase aquosa para pH 1 com HC1 aquoso 5 M e extraiu-se com acetato de etilo. Lavaram-se as fases orgânicas .combinadas com NaCl aquoso, saturado e secou-se sobre N32S04. A evaporação in vacuo originou o composto do título, EM (m/e): 336,1 ([M-H]&quot;, 100 %) (e) (3-[4- (4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]- 4-(4-metoxi-benziloxi)-benzeno-sulfonamida A uma solução de 3,5 mmole ' do ácido 2-(4-metoxi-benziloxi) -5-sulfamoil-benzóíco, no seio de 4 mL de 189 dimetilformamida e 12 mL de THF, adicionou-se'5,3 mmole de TBTU, 17,5 mmole de N-etildi-isopropilamina e 3,5 mmole de 3-fluoro-4-piperazin-l-il-benzonitrilo (patente de invenção W09625414). Agitou-se então a mistura reaccional à TA durante 1 hora, concentrou-se in vacuo e purificou-se por cromatografia em gel de silica (eluente: gradiente de acetato de etilo/heptano}, para se obter o composto do titulo, EM (m/e): 525,1 (M+H+) (f) (3-[4-(4-Ciano-3-fluoro-fenil)-piperazino-l-carbonil]- 4-hidroxi-benzeno-sulfonamidaAmmonia gas was bubbled through a solution of 107 mmol of 5-chlorosulfonyl-2-hydroxybenzoic acid in 250 mL of acetone at 0 ° C for 2 hours. After . gaseous argon was bubbled through the reaction mixture for 1 hour to purge excess ammonia. The mixture was then diluted with water, the pH adjusted to 14 by the addition of 5M aqueous NaOH solution, and the mixture was extracted with ether / ethyl acetate (1: 1). the aqueous layer was concentrated with HCl, saturated with NaCl and extracted twice with THF. The combined THF extracts were dried with Na2 SO4 &gt; 4. Evaporation of the solvent in vacuo followed by drying of the residue by heating at 60 ° C overnight in vacuo afforded the title compound. (B) 2-Hydroxy-5-sulfamoyl-benzoic acid methyl ester To 62 mmole of 2-hydroxy-5-sulfamoyl-benzoic acid, in 80 mL of THF was added 80 mL. mmol of CDI was added and the mixture was heated at 50 ° C for 1 hour. 616 mmol of methanol was then added and the mixture was heated at 50 ° C for 16 hours. The mixture was then cooled to room temperature, concentrated in vacuo and the residue purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). The product containing the fractions was concentrated in vacuo and the residue was suspended in ethyl acetate and washed with aqueous NaHCO 3 solution. The organic phase was dried with Na2 SO4 and concentrated in vacuo to give the title compound. (C) 2- (4-Methoxy-benzyloxy) -5-sulphamoyl-benzoic acid methyl ester To the 4.8 mmole of 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol of 4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 mL THF was added 5.2 mmol of di- tert-butyl ester and the mixture was stirred at RT for 2 hours. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluent: ethyl acetate / heptane gradient) to provide the title compound. D) 2- (4-Methoxy-benzyloxy) -5-sulphamoyl-benzoic acid To 2.5 mmole of 2- (4-methoxy-benzyloxy) (4-methoxy-benzyloxy) -5-sulphamoyl-benzoic acid in 6 mL of THF was added 5 mL of 2M aqueous NaOH and the mixture was heated at 60 ° C for 30 minutes. The mixture was then cooled to rt. And extracted twice with ethyl acetate. The aqueous phase was acidified to pH 1 with 5M aqueous HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl and dried over N 2 SO 4. Evaporation in vacuo afforded the title compound, MS (m / e): 336.1 ([MH] &quot;, 100%) (e) (3- [4- (4-cyano-3-fluoro-phenyl) To a solution of 3.5 mmole of 2- (4-methoxy-benzyloxy) -5-sulphamoyl-benzoic acid in methylene chloride of 4 mL of dimethylformamide and 12 mL of THF was added 5.3 mL of TBTU, 17.5 mmol of N-ethyldiisopropylamine and 3.5 mmol of 3-fluoro-4-piperazin-1-yl The reaction mixture was then stirred at RT for 1 hour, concentrated in vacuo and purified by silica gel chromatography (eluent: ethyl acetate / heptane gradient) to afford the title compound as a white solid. (m / e): 525.1 (M + H +) (f) (3- [4- (4-Cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] - 4-hydroxy-benzenesulfonamide

Fez-se borbulhar hidrogénio gasoso através de . uma solução de 1,0 mmole de (3-[4-(4-ciano-3-fluorofenil)-piperazino-l-carbonil]-4-(4-metoxi-benziloxi)-benzeno-sul-fonamida, no seio de 40 mL de THF contendo 50 mg de paládio em carvão a 10 % e algumas gotas de ácido acético, durante 6 horas, à TA. Depois fez-se a purga da mistura reaccional com árgon, filtrou-se através de celite e coricentrou-sè o filtrado in vacuo. Purificou-se o resíduo por cromatografia em gel de sílica (eluente: gradiente de metanol/dicloro-metano), para se obter o composto do título. EM (m/e): 403,1 ( [M-H]&quot;, 100 %)Hydrogen gas was bubbled through. A solution of 1.0 mmol of (3- [4- (4-cyano-3-fluorophenyl) piperazine-1-carbonyl] -4- (4-methoxy-benzyloxy) -benzenesulfonamide in 40 ml of THF containing 50 mg of 10% palladium-on-charcoal and a few drops of acetic acid for 6 hours at RT. The reaction mixture was then purged with argon, filtered through celite and corroded The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane gradient) to give the title compound. MS (m / e): 403.1 ([MH] &quot;, 100%)

Em analogia com os exemplos 6.38 (e) e (f), prepararam-se os compostos 6.39 e 6.40 do quadro que se segue, a partir do ácido 2-(4-metoxi-benziloxi)-5-sulfamoil-benzóico e da pipérazina apropriada, seguido de hidrogenólise com paládio em carvão catalítico:In analogy to examples 6.38 (e) and (f), compounds 6.39 and 6.40 of the following table were prepared from 2- (4-methoxy-benzyloxy) -5-sulphamoyl-benzoic acid and the pipetrazine followed by hydrogenolysis with palladium on catalytic charcoal:

Exemp. Nome Sistemático Materiais Iniciais EM (m/e) 6.39 3-[4-(4-ciano-2-fluoro-fènil)-piperazino-l-carbonilj-4-hidroxi-benzeno-sulfonamida 3-fluoro-4-piperazin-l-ii-benzonitrilo (patente de invenção WO 9625414) 403,1 (M-H) 190 3-[4-(2-fluoro-4-metano-sulfonil- 1-(2-fluoro-4-metano- 456,2 6.40 fenil)-piperazino-l-carbonil]-4- sulfonil-fenil)- (M-H) hidroxi-benzeno-sulf onamida piperazina (comercial)Exemp. 1-methyl-3- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide 3-fluoro-4-piperazin-1 (4H) -benzonitrile (WO 9625414) 403.1 (MH) 190 3- [4- (2-fluoro-4-methanesulfonyl-1- (2-fluoro-4-methano- ) -piperazine-1-carbonyl] -4-sulfonyl-phenyl) - (MH) -hydroxy-benzenesulfonamide piperazine (commercial)

Exemplo 622Example 622

Preparação de 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4-isobutoxi-benzeno-sulfonamida A 0,1 mmole ' de (3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil] -4-hidroxi-benzeno-sulfonamida . {composto 6.38), 0,5 mmole de 2-metil-l-propanol e 0,3 mmole de difenil-2-piridilfosfina, no seio de 4 mL dê THF, adicionou-se 0,3 mmole de azodicarboxilato de di-terc-butilo e agitou-se a- mistura a 60 °C, durante 4 horas. Diluiu-se então a mistura com acetato de etilo e lavou-se duas vezes com HC1 aquoso 5 M e depois com uma solução de NaCl saturada, aquosa. Secou-se então a fase orgânica com Na2SC&gt;4 e concentrou-se iri yacuo. Triturou-seo resíduo no seio de éter, para se obter o composto do título. EM (m/e) : 459,2 ( [M-H]~, 100 %)Preparation of 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-benzenesulfonamide To 0.1 mmole of (3- [4- (4-cyano -3-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3 mmol diphenyl 2- pyridylphosphine in 4 mL of THF was added 0.3 mmol of di-tert-butyl azodicarboxylate and the mixture was stirred at 60 ° C for 4 hours. The mixture was then diluted with ethyl acetate and washed twice with 5M aqueous HCl and then with a saturated aqueous NaCl solution. The organic phase was then dried with Na2 SO4 and concentrated in vacuo. The residue was triturated in ether to give the title compound. MS (m / e): 459.2 ([M-H] -, 100%)

Em analogia com o exemplo 622, prepararam-se os compostos .623 a 632 do quadro que se segue, a partir dos compostos 6.3,8 a 6.4Ό e do álcool apropriado:In analogy to example 622, compounds .623 to 632 of the following table were prepared from compounds 6.3.8 to 6.4 and the appropriate alcohol:

Exemp. N° . Home Sistemático Materiais Iniciais PM encont. (M+H) 623 3-[ 4- {4-ciano-3-fluoro-fenil} -piperazino-l-carbonil] -4-cicloperitÍloxi-. benzeno-sulfonamida 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]-4-hidroxi-benzeno-sulfonamida (composto 6.38) e ciclopentanol 471,3 (M-H) 624 3- [4- (4-cianò-2-fluoro-fenil) -píperazino-1-cartoonil]-4-isopropoxi-benzeno-sulfonamida 3-[4-(4-cíano-2-fluoro-fenil)-piperazino-l-carbonil]-4-hidroxi-benzeno-sulfonamida (composto 6.39) e 2-propanol 445,2 (M-H) 191 625 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil] -4-isobutoxi-benzeno-sulfonamida 3-[4-(4-ciano-2-fluoro-fenil}-piperazino-l-carbonil]-4-hidroxi-benzeno-sulfonamida (composto 6.39} e 2-metil-l-propanol 459,2 (M-H) 626 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil] -4-ciclopentiloxi-benzeno-sulfonamida 3-[4-(4-ciano-2-fluoro-fenil)-piperazino-l-carbonil]-4-hidroxi-benzeno-sulfonamida (composto 6.39) e ciclopentanol 471,3 (M-H) 627 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-isobutoxi-benzeno-sulfonamida 3- [4- (2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-hidroxi-benzeno-sulfonamida (composto 6.40) e 2-metil-l-propanol 512,3 (M-H) 628 4-ciclopentiloxi-3-[4-(2-fΓuoro-4-metano-sulfonil-fenil)-piperazina-1-carbonil]-benzeno-sulfonamida 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-hidroxi- benzeno·-sulfonamida (composto 6,40) e ciclopentanol 524,5 (M-H) 629 3- [4- (4-ciano-3-fluoro-fenil)-piperasino-1-carbonil]“4-isopropoxi-benzeno-sulfonamida . 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]-4-hidroxi-bénzeno-sulfonamida (composto 6.38) e 2-propanol 445,1 (M-H) 630 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-1-carbonil]-4- ciclobutilmetoxi-benzeno-sulfonamida . 3-[4-(4-ciano-3-fluoro-fenil)-piperazino-l-carbonil]-4-hidroxi-benzeno-sulfonamida (composto 6,38).e ciclobutanometanol 471,3 (M-H) 631 ' 3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-4-isopropoxi-benzeno-sulfonamida 3- [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-hidroxi-benzeno-sulfonamida (composto 6.40) e 2-propanol 498,4 (M-H) 632 4-ciclcbutílmstoxi-3-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazino-1-carbonil]-benzeno-sulfonamida 3-[4- (2-fluoro-4-metano-sulfonil-fenil)-piperazino-l-carbonil] -4-hidroxi-benzeno-sulfonamida (composto 6.40) e o iclobutanometanol 524,5 (M-H)Exemp. No. Home Systematic Initial Materials PM found. (M + H) 623 3- [4- (4-Cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cycloperitetyloxy-. benzenesulfonamide 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.38) and cyclopentanol 471.3 (MH) 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbanyl] -4-isopropoxy-benzenesulfonamide ] -4-hydroxy-benzenesulfonamide (compound 6.39) and 2-propanol 445.2 (MH) 191 625 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.39) and 2-methyl-1-propanol , 2 (MH) 626 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-benzenesulfonamide 3- [4- (4-cyano-2-fluoro 1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.39) and cyclopentanol 471.3 (MH) 627 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine- piperazino-1-carbonyl] -4-isobutoxy-benzenesulfonamide 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzene 2-methyl-1-propanol 512.3 (MH) 628 4-cyclopentyloxy-3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl chloride (compound 6.40) and 2-methyl- ] -benzenesulfonamide 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.40) and cyclopentanol 524.5 (MH) 629 3- [4- (4-cyano-3-fluoro-phenyl) -piperazino-1-carbonyl] -4-isopropoxy-benzenesulfonamide. 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxybenzenesulfonamide (compound 6.38) and 2-propanol 445.1 (MH) 630 3- [4- - (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-benzenesulfonamide. 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.38) and cyclobutanemethanol 471.3 (MH) 3- [4- (2-Fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-benzenesulphonamide [4- (2-fluoro-4-methanesulfonyl- piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.40) and 2-propanol 498.4 (MH) 632 4-Cyclobutylmethyl-3- [4- (2-fluoro-4-methanesulfonyl-phenyl ) -piperazine-1-carbonyl] -benzenesulfonamide 3- [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine-1-carbonyl] -4-hydroxy-benzenesulfonamide (compound 6.40) and or iclobutanemethanol 524.5 (MH)

Exemplo 7.1Example 7.1

Preparação de 3-piperazin-l-il-5-trifluorometil-piridazina 192 (a) 3-Cloro-5-trifluorometil-piridazinaPreparation of 3-piperazin-1-yl-5-trifluoromethyl-pyridazine 192 (a) 3-Chloro-5-trifluoromethyl-pyridazine

Adicionou-se 5-trifluorometil-piridazin-3-ol [244268-34-6] (1 g) a uma solução agitada de cloreto de fosforiloxi e agitou-se a mistura reaccional a 80 °Cr durante .1 hora. Passado este tempo, deixou-se a mistura reaccional arrefecer para a temperatura ambiente, verteu-se em gelo e, passados 5 minutos, extraiu-se duas vezes no seio de uma solução aquosa com diclorometano. Secaram-se as fases orgânicas combinadas, com sulfato, de sódio e concentrou-se in vacuo. Destilou-se o resíduo num aparelho de Kugelrohr (pb &gt; 80-100 °C @ 12 mBar) , para se obter o composto do titulo (0,26 g). EM (m/e): 182,0 (b) . Éster terc-butllico do ácido 4-(5-trif.luorometil-piri- dazin-3-il)-piperazino-l-carboxílico5-Trifluoromethyl-pyridazin-3-ol [244268-34-6] (1 g) was added to a stirred solution of phosphoryloxy chloride and the reaction mixture was stirred at 80 ° C for 1 h. After this time, the reaction mixture was allowed to cool to room temperature, poured into ice and, after 5 minutes, extracted twice with an aqueous solution of dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was distilled in a Kugelrohr apparatus (bp> 80-100øC> 12 mbar) to provide the title compound (0.26 g). MS (m / e): 182.0 (b). 4- (5-Trifluoromethyl-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

Adicionou-se 3-cloro-5-trifluorometil-piridazina (200 mg) ao éster terc-butílico do ácido piperazino-l-carboxílico (231 mg), no seio de dimetilacetamida (3 mL) e agitou-se a mistura reaccional a 100 °C, durante 3 horas. Passado este tempo, deixou-se a mistura reaccional arrefecer para a temperatura ambiente e diluiu-se com acetato de etilo. Filtrou-se o sólido e lavou-se com acetato de etilo. Depois concentrou-se o filtrado in vacuo e purificou-se então por meio de cromatografia em coluna . (Si02, heptano/EtOAc), para se obter o composto do título, sob a forma de ura. sólido branco (364 mg). EM (m/e): 333,4 (M+H+, 100 %) (c) 3-Piperazin-l-il-5-trifluorometil-piridazina3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL) and the reaction mixture was stirred at 100 ° C for 3 hours. After this time, the reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The solid was filtered and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography. (SiO2, heptane / EtOAc) to provide the title compound as a ura. white solid (364 mg). MS (m / e): 333.4 (M + H +, 100%) (c) 3-Piperazin-1-yl-5-trifluoromethylpyridazine

Dissolveu-se o éster terc-butílico do ácido 4-(5-trifluorometil-piridazin-3-il)-piperazino-l-carboxílico (45 mg), no seio de diclorometano (0,5 mL) e adicionou-se ácido 193 trifluoroacético (0,5 raL) . Agitou-se a mistura reaccional durante 30 minutos antes.de se concentrar in vacuor para se obter o composto . do titulo impuro, que se utilizou directamente na etapa seguinte sem mais purificação ou análise..4- (5-Trifluoromethyl-pyridazin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (45 mg) was dissolved in dichloromethane (0.5 mL) and 193 trifluoroacetic acid (0.5æl). The reaction mixture was stirred for 30 minutes before concentration in vacuo to provide the compound. of the impure titre, which was used directly in the next step without further purification or analysis ..

Exemplo 7.2Example 7.2

Preparação do ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-1,l^dimetil-etoxi)-benzóicoPreparation of 5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethylethoxy) -benzoic acid

Ao ácido 2-fluoro-5-metano-sulfonil-benzóico [247569-56-8] (600 mg), no seio de dimetílacetamida (10 mL ), adicionou-se carbonato de césio a 170 °C. Adicionou-se primeiro à mistura reaccional 2-trifluorometil-propanol (0,9.4 mL) seguido de mais' 0,47 mL de 2'4 em 24 horas. Após um total de 72 horas, ' acidificou-se a mistura reaccional por adição de' .ácido fórmico, concentrou-se in vacuo e purificou-se por CLER preparativa, para se obter o composto do titulo, sob a forma de um sólido castanho claro (897 mg). EM (m/e) 325,3- (M-H, 100 %)To 2-fluoro-5-methanesulfonyl-benzoic acid [247569-56-8] (600 mg) in dimethylacetamide (10 mL) was added cesium carbonate at 170 ° C. 2-Trifluoromethyl-propanol (0.9.4 mL) was added first to the reaction mixture followed by an additional 0.47 mL of 2.4 in 24 hours. After a total of 72 hours, the reaction mixture was acidified by the addition of formic acid, concentrated in vacuo and purified by preparative HPLC to give the title compound as a brown solid clear (897 mg). MS (m / e) 325.3- (M-H, 100%)

Exemplo 7.3Example 7.3

Preparação de 5-metano-sulfonil-2-piperázin.-l--il-pirimidina (a) Cloreto de 3-dimetllamino-2-metano-sulfonil-alilideno-dimetil-amónioPreparation of 5-methanesulfonyl-2-piperazin-1-yl-pyrimidine (a) 3-Dimethylamino-2-methanesulfonylalilidene dimethyl ammonium chloride

Ao ácido sulfonil-acético (1,5 g), no seio de dimetil-formamida, adicionou-se, lentamente, oxicloreto fosforoso, durante 5 minutos e deixou-se a mistura reaccional em agitação a 70 °C, durante 1 hora e depois à temperatura ambiente, durante a . noite. Verteu-se em seguida, 194 directamente, a mistura reaccional sobre uma coluna de cromatografia curta (SÍO2, 100 g), eluindo-se, sucessivamente, com 50Q mL de EtOAc, THF, EtOAc/EtOH (50/50), EtOH e, finalmente, MeOH, para se obter o composto do titulo (1,58 g) . EM (m/e) : 204,9 (M+) (b) 5-Metano-sulfonil-2-piperazin-l-il-pirimidinaTo the sulfonyl acetic acid (1.5 g) in dimethylformamide, phosphorus oxychloride was slowly added, over 5 minutes, and the reaction mixture was allowed to stir at 70 ° C for 1 hour and then at room temperature, for 1 hour. night. The reaction mixture was then directly added on a short chromatography column (SiO 2, 100 g), eluting successively with 50% EtOAc, THF, EtOAc / EtOH (50/50), EtOH and , finally MeOH, to give the title compound (1.58 g). MS (m / e): 204.9 (M +) (b) 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine

Preparou-se o composto do titulo em analogia com o exemplo 2.25, utilizando cloreto de 3-dimetilamino-2-metano-sulfonilalilideno-dimetil-amónio como material inicial. EM (m/e): 243,1 (M+H+, 100 %)The title compound was prepared in analogy to example 2.25 using 3-dimethylamino-2-methanesulfonylalidene dimethyl ammonium chloride as the starting material. MS (m / e): 243.1 (M + H +, 100%)

Exemplo 7.4Example 7.4

Preparação do ácido 1-{5-raetano~sulfonil-piridin-2-il)-piperazino-trifluoro-acéticoPreparation of 1- {5-methanesulfonyl-pyridin-2-yl) -piperazine-trifluoro-acetic acid

Preparou-se o composto do titulo em analogia com o exemplo 7.1 (b-c), a partir de 2-bromo-5-(metano-sulfonil)-piridina e do éster terc-butilico do ácido piperazino-1-carboxílico. EM (m/e): 242,1 (M+H+, 100 %)The title compound was prepared in analogy to example 7.1 (b-c) from 2-bromo-5- (methanesulfonyl) pyridine and piperazine-1-carboxylic acid tert-butyl ester. MS (m / e): 242.1 (M + H +, 100%)

Em analogia com o exemplo 5, prepararam-se os compostos 633 a 644 do quadro que se segue, a partir dos derivados de ácido e derivados de piperazina:In analogy to example 5, compounds 633 to 644 of the following table were prepared from the acid derivatives and piperazine derivatives:

Exemp. N°. Nome Sistemático Materiais Iniciais PM encont. (M+H) 633 rác-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(5-trifluorometil-piridazin-trifluorometil-piridazin-3-il)-piperazin-l-il]-metanona 3-piperazin“l-il“5-trifluorometil-piridazina (coirposto 7.1) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) 527,0 195 634 [5-metano-sulfonil-2-(2,2,2-trifluoro-1,1-dimetil-etoxi) -fenil]-[4-(5-trifluorometil-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometil-pirimidina (composto 2.25) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-1,1-dimetil-etoxi)-benzóico (composto 7.2) 541,0' 635 (5-metano-sulfonil-2- ( (S) -2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4- (5- trifluorometil-pirimidin-2-11)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometil-pirimidina (composto 2.25) e ácido 5-metano-sulfonil-2-((3)-2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.6) 527,2 636 [5-metano-sulfonil-2-{(R)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(5-tr.ifluoroinetil-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-triflnorometil-pirimidina (composto 2.25) e ácido 5-metano-sulfonil-2-((R)—2,2,2— trifluoro-l-metil-etoxi)-benzóico (composto 5.7·) 527,2 637 [4- (3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-1,1-dimetil-. etoxi)-fenil]-metanona 1-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazina (composto 5.5) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-benzóico (composto 7.2) 558,2 638 [5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(5-trifluorometil-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometil-pirimidina (composto 2.25) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzóico (composto 1.5) 513,3 639 (2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4~ (5-trifluorometil-pirimidin-2-il)-piperazin-l-il]-metanona 2-piperazin-l-il-5-trifluorometi1-pirimidina (composto 2.25) e ácido 2-ciclopropilmetoxi-5-metano-sulfonil-benzóico (composto 1.4) 485,4 640 [4-(2,5-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimeti.l-etoxi)-fenil]-metanona ácido 1-(2,5-difluoro-4-metano-sulfonil-fenil)piperazino-trifluoro-acético (composto 2.20) e ácido 5-metano-sulfonil-2- (2,2,2-trifluoro-l, 1-dimetil-etoxi)-benzóico (composto 7.2) 585,3 641 [4-(2,3-difluoro-4-metano-sulfonil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluOro-l,1- 1-(2,3-fenil)-4-metano-sulfonil-fenil)-piperazina (composto 5.3) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil- 585,3 196 dimetil-etoxi)-fenil]-metanona etoxi)-benzóico (composto 7.2) 642 [4- (2, 6-difluoro-4-metano-, sulfonil-fenil)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-fenil]-metanona ácido 1-(2,6-difluoro-4-metano-sulfonil-fenil)piperazino-trifluorò-acético (composto 2.23) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-benzóico (composto 7.2) 585,2 643 rac~[4-(5-metano-sulfonil-pirimldln-2-il)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l-etil-etoxi)-fenil]-metanona 5-metano-sulfonil-2-piperazin-l-il-pirimidina (composto 7.3) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil etoxi)-benzóico (composto 3.1) 537,3 644 rac-[4-(5-metano-sulfonil-piridin-2-il)-piperazin-l-il] - [5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona ácido 1-(5-metano-sulfonil-piridin-2-íl)-piperazino-trifluoro-acético (composto 7.4) e ácido rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 3.1) '536,3 'Exemp. No. Systematic Name Initial Materials PM found. (5-trifluoromethyl-pyridazin-1-yl) -piperidine-5-carboxylic acid (M + H) 3-yl) -piperazin-1-yl] -methanone 3-piperazin-1-yl] -5-trifluoromethyl-pyridazine (co-derivative 7.1) and rac-5-methanesulfonyl-2- (2,2,2- (5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] - [4-methyl-ethoxy] -benzoic acid Pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (compound 2.25) and 5-methanesulfonyl-2- (2- , 2,2-trifluoro-1,1-dimethylethoxy) benzoic acid (compound 7.2) 541.0 635 (5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro- methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyrimidin-2-11) -piperazin-1-yl] -methanone 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (compound 2.25) and 5-methanesulfonyl-2 - ((3R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.6) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl) pyrimidin-2-yl) -piperazin-1-yl] -methanone 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (compound 2.25) and 5-methanesulfonyl-2 - ((R) -2- (4-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -amide [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl- ethoxy) -phenyl] -methanone 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5.5) and 5-methanesulfonyl-2- (2,2,2- 1-dimethyl-ethoxy) -benzoic acid (compound 7.2) 558.2 638 [5-methanesulfonyl-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyrimidine -2-yl) -piperazin-1-yl] -methanone 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine (compound 2.25) and 5-methanesulfonyl-2- (2,2,2- ethoxy) -benzoic acid (compound 1.5) 513.3 639 (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (5-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-yl] -methanone 2 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (compound 1.4) 485.4 640 [4- (2,5-difluoro-4-methane sulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] -methanone 1- ( 2,5-difluoro-4-methanesulfonyl-phenyl) -piperazine-trifluoroacetic acid (compound 2.20) and 5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl- yl) - [5-methanesulfonyl-2- (2,3-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] 2,2-trifluoro-1,1- (2,3-phenyl) -4-methanesulfonyl-phenyl) -piperazine (compound 5.3) and 5-methanesulfonyl-2- (2,2,2- dimethyl-ethoxy) -phenyl] -methanone ethoxy) -benzoic acid (compound 7.2) 642 [4- (2,6-difluoro-4-methano-, sulfonyl-phenyl) 1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] -methanone 1- (2,6-Difluoro-4- 5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -benzoic acid (compound 7.2) , 2 643 rac- [4- (5-methanesulfonyl-pyrimidin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-ethyl 2-piperazin-1-yl-pyrimidine (compound 7.3) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methoxyphenyl) methyl-ethoxy) -benzoic acid methyl ester (compound 3.1) 537.3 644 rac- [4- (5-methanesulfonyl-pyrid n-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1- (5-methane 2-yl) -piperazine-trifluoroacetic acid (compound 7.4) and rac-5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 3.1) '536.3'

Exemplo 645Example 645

Preparação de (2-aliloxi-5-nitro-fenil)-[4-(4-trifluorome-til-fenil)-piperazin-l-il]-metanonaPreparation of (2-allyloxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone

Preparou-se o composto do titulo em analogia com o exemplo 62, a partir de (2-hidroxi-5-nitrofenil)-[4-(4-tri-fluorometilfenil)-piperazin-l-il]-metanona (composto 2.1) e brometo de ciclopropilo. EM (m/e): 436,5 (MH+, 100 %)The title compound was prepared in analogy to example 62 from (2-hydroxy-5-nitrophenyl) - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone (compound 2.1) and cyclopropyl bromide. MS (m / e): 436.5 (MH +, 100%)

Exemplo 7.5Example 7.5

Preparação do ácido 2-benziloxi-5-metano-sulfonil-l&gt;enzóicoPreparation of 2-benzyloxy-5-methanesulfonyl-1-en-

Preparou-se o composto do titulo em analogia com o exemplo 2.10, a partir de 5-(metano-sulfonil)-salicilato de metilo e álcool benzilico. EM (m/e): 305,3 (M-H, 100'%)The title compound was prepared in analogy to example 2.10 from 5- (methanesulfonyl) -salicylate and benzyl alcohol. MS (m / e): 305.3 (M-H, 100%)

Exemplo 646 197Example 646

Preparação de (2-benziloxi-5-metano-sulfonil-fenil) -[4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -meta-nonaPreparation of (2-benzyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone

Preparou-se o composto do título em analogia' com o exemplo 5, a partir de 1-(3-fluoro-5-trifluorometil-pi-ridín-2-il·}-piperazina (composto 5.5) e ácido 2-benzil-oxi-5-metano-sulfonil-benzóico (composto 7.5). EM (m/e): 538,4 (MH4, 100 %)The title compound was prepared in analogy to example 5 from 1- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine (compound 5.5) and 2-benzyl- oxy-5-methanesulfonyl-benzoic acid (compound 7.5) MS (m / e): 538.4 (MH4, 100%)

Exemplo 647Example 647

Preparação de (2-benziloxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanonaPreparation of (2-benzyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone

Preparou-se o composto do título em analogia com o exemplo 5, a partir de 1-(2-fluoro-4-metano-sulfonil-fe-nil)-piperazina (comercial) e ácido 2-benziloxi-5-metano-sulfonil-benzóico (composto 7.5). EM (m/e): 547,4 (MH4, 100 %)The title compound was prepared in analogy to example 5 from 1- (2-fluoro-4-methanesulfonyl-phenyl) -piperazine (commercial) and 2-benzyloxy-5-methanesulfonyl- (compound 7.5). MS (m / e): 547.4 (MH +, 100%)

Exemplo 648Example 648

Preparação de [4-(2-fluoro-4-metano-sulfonil-fenil) -piperazin-l-il]- (2-hidroxi-5-metano-sulfonil-fenil)-metanonaPreparation of [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-hydroxy-5-methanesulfonyl-phenyl) -methanone

Hidrogenou-se, à pressão atmosférica, à temperatura ambiente, durante 2 horas, uma mistura de 0,915 mmole de (2-benziloxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-meta-no-sulfonil-fenil)-piperazin-l-il]-metanona, 0,05 mmole de paládio em carvão (10 %), no seio de 12,5 mL de metanol. Após a adição do clorofórmio, filtrou-se a mistura e evaporou-se o dissolvente, para se obter o composto do título. EM (m/e) : 474,3 (M+NH44, 100 %) 198A mixture of 0.915 mmol of (2-benzyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methylethyl) sulfonyl-phenyl) -piperazin-1-yl] -methanone, 0.05 mmol of palladium on charcoal (10%) in 12.5 mL of methanol. After addition of the chloroform, the mixture was filtered and the solvent was evaporated to give the title compound. MS (m / e): 474.3 (M + NH 4, 100%) 198

Exemplo 7.6Example 7.6

Preparação de 5-piperazin-l-il-2-trifluorometil-pirimidina (a) 5-Cloro-2-trifluorometil-pirimidina : A uma solução de 38 mmole' de trifluoroacetamidina., no seio de 70 ' mL de acetonitrilo, adicionou-se 37,92 mmole de fosfato de hexaflúor e ((Z)-2-cloro-3-dimetilamino-alilide-no)-dimetil-amónio (CAS: 291756-76-8), seguido de 45,5 mmole de trietilamina. Agitou-se a solução amarela à temperatura ambiente,· durante 5 horas,., depois verteu-se em água e extraiu-se 3 vezes' com éter. Secaram-se os extractos combinados sobre sulfato de sódio, filtrou-se e destilou-se a 760 mm Hg, para se obter o composto do título. EM (m/e): 182,2 (M+, 1Ό0 %) (b) Éster terc-butilico do ácido 4-(2-trifluorometil-pirimidin-5-il)-piperazino-l-carboxilicoPreparation of 5-piperazin-1-yl-2-trifluoromethyl-pyrimidine (a) 5-Chloro-2-trifluoromethyl-pyrimidine: To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile, and ((Z) -2-chloro-3-dimethylamino-allyl) -dimethylammonium phosphate (CAS: 291756-76-8) followed by 45.5 mmol of triethylamine. The yellow solution was stirred at room temperature for 5 hours then poured into water and extracted 3 times with ether. The combined extracts were dried over sodium sulfate, filtered and distilled at 760 mm Hg to give the title compound. MS (m / e): 182.2 (M +, 10%) (b) 4- (2-Trifluoromethyl-pyrimidin-5-yl) -piperazine-1-carboxylic acid tert-

Adicionou-se 0,26 mmole de 5-cloro-2-trifluorometil-pirimidina a 0,26 mmole de éster terc-butílico do ácido piperazino-l-carboxílico, no seio de 1,5 mL de dimetilacetamida e agitou-se a mistura reaccional a 150 °C, durante 10 minutos, num forno de microondas. Passado este tempo, concentrou-se a mistura. reaccional e depois puri-ficou-se o resíduo por cromatograf ia em coluna (S1O2, heptano/EtOAc), para se obter o composto do título. EM (m/e) : 333,2 (M+H+, 100 %) (c) 5-Piperazin-1-11-2-trifluorometil-pirimidina0.26 mmol of 5-chloro-2-trifluoromethyl-pyrimidine was added to 0.26 mmol of piperazine-1-carboxylic acid tert-butyl ester in 1.5 mL of dimethylacetamide, and the mixture reaction at 150 ° C for 10 minutes in a microwave oven. After this time, the mixture was concentrated. The residue was purified by column chromatography (SiO2, heptane / EtOAc) to give the title compound. MS (m / e): 333.2 (M + H +, 100%) (c) 5-Piperazin-1-11-2-trifluoromethyl-pyrimidine

Preparou-se o composto do título em analogia com o exemplo 7.1 (c) , a partir do éster terc-butílico do ácido 199 4-(2-trifluorometil-pirimidin-5-il)-piperazino-l-carboxí-lico. EM (m/e): 233,0 (M+H+, 100 %)The title compound was prepared in analogy to example 7.1 (c) from 4- (2-trifluoromethyl-pyrimidin-5-yl) -piperazine-1-carboxylic acid tert-butyl ester. MS (m / e): 233.0 (M + H +, 100%)

Exemplo 7.7Example 7.7

Preparação de 5'-trifluoroiiietil-3,4,5,6-tetra-hidro-2H- [1,2r ]bipxrazinxló (a) 2-Bromo-5-trifluorometll-plrazina A uma suspensão de 0,423 mmole de brometo de cobre (II), no seio de THF (1 mL) , adicionou-se, gota a gota, 0,51 mmole de terc-butilnitrito, a 0 °C, durante 2 minutos. Adicionou-se, gota a gota, durante 5 minutos, a 0 °C, 0,37 mmole de 5-trifluorometil-pirazin-2-ilamina (CAS:' 69816-38-2; patente de invenção WO 9518097), em solução, no seio de THF (0,5 mL) .· Agitou-se a mistura a 0 °.C, durante 1 hora, à temperatura ambiente, durante 21 horas e parou-se a reacção com água. Extraiu-se a fase aquosa com éter. Secaram-se os extractos combinados sobre sulfato de sódio, filtrou-se e concentrou-se à pressão atmosférica. Purificou-se então o resíduo por cromatografia em coluna (SÍO2, éter), para se obter o composto do titulo. (b) . 5'-Trifluorometil-3,4,5,6-tetra-hidro-2H-[1,2']- bipira-ziniloPreparation of 5'-Trifluoroethyl-3,4,5,6-tetrahydro-2H- [1,2] biprazolexl (a) 2-Bromo-5-trifluoromethyl-prazine To a suspension of 0.423 mmole of copper bromide ( II) was dissolved in THF (1 mL), tert-butylnitrite (0.51 mmol) was added dropwise at 0 ° C for 2 minutes. 5-Trifluoromethyl-pyrazin-2-ylamine (CAS: 69816-38-2, WO 9518097) was added dropwise over 5 minutes at 0 ° C in solution was dissolved in THF (0.5 mL). The mixture was stirred at 0 ° C for 1 hour at room temperature for 21 hours and quenched with water. The aqueous phase was extracted with ether. The combined extracts were dried over sodium sulfate, filtered, and concentrated at atmospheric pressure. The residue was then purified by column chromatography (SiO2, ether) to give the title compound. (B) . 5'-Trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2 '] - bipyrazinyl

Preparou-se . o composto do título em analogia com o exemplo 7.6 (b-c) , a partir de 2-bromo-5-trifluorometil- pirazina EM (m/e): 233,0 (M+H+, 100 %)It was prepared. the title compound in analogy to example 7.6 (b-c) from 2-bromo-5-trifluoromethylpyrazine MS (m / e): 233.0 (M + H +, 100%).

Exemplo 7.8Example 7.8

Preparação de 3-pipérazin-l-il-6-trifluorometil-piridazina 200Preparation of 3-pipezrazin-1-yl-6-trifluoromethyl-pyridazine 200

Preparou-se o composto do titulo em analogia com o exemplo 7.6 {b-c), a partir de 3-cloro-6-trifluorometil- piridazina &lt;CAS: 258.506-68-2} . ‘ EM (m/e):. 233,0 (M+H+, 100 %)The title compound was prepared in analogy to example 7.6 (b-c), from 3-chloro-6-trifluoromethyl-pyridazine &lt; CAS: 258,506-68-2}. ' In me):. 233.0 (M + H +, 100%)

Em analogia com o exemplo 5, prepararam-se os compostos 649 a 660 do quadro que se segue, a partir dos derivados de ácido e derivados de piperazina:In analogy to example 5, compounds 649 to 660 of the following table were prepared from the acid derivatives and piperazine derivatives:

Exemp. N°. Nome Sistemático Materiais Iniciais PM encont. (M+H) 649 [5-metano-sulfonil-2-((S) - . 2,2,2-trifluoro-l-metil-etoxi)-fenil]- (4- (2-tri-fluorometil-pirimidin-5-il) -piperazin-l-il]-metano-na 5-piperazin-l-il~2-trifluorome-til-pirimidina (composto 7.6) e. ácido 5-metano-sulfonií-2-((S)— 2,2,2-trifluoro-l-metil-etoxi)-benzóico (composto 5.6) 527,2 650 [5-metano-sulf.onil-2- (R) -2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(2-triflu-orometil-pirimidin-5-il) -piperazin-l-il]-metanona 5-piperazin-l-il-2-trifluorometil-pirimidina (composto 7.6) e· ácido 5-metano-sulfonil-2-{(R)-2,2,2-trifluoro-1-metil-etoxi)-benzóico. (composto 5.7) 527,0 651 (2-isopropoxi-5-metano-sulfonil-fenil) - [4-.(2-trifluoròmetil-pirimidin-5-il)-piperazin-l-il]-metanona 5-piperazi.n-l-il-2-trif luoro-metil-pirimidina (composto 7,6) e ácido 2-isopropoxi-5-metano-sulfonil-beiizóico (composto 1.2) 473,0 652 . [5-metano-sulfonil-2-((S) — 2,2,2-trifluoro-l-metil-etoxi)-fenil] - (5'.-trifluorometil-2,3,5,6-tetrá-hidro-[1,2']-bipírazinil-4-il)-metanona 5'-trifluorometil-3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinilo (composto 7.7) e ácido. 5-metano-sulfonil-2-((S)-2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 5.6) 527,2 653 [5-metano-sulfonil-2-((R)-2, 2,2-trifluoro-l-metil-etoxi)-fenil]-(5'-trifluorometil-2,3,5,6-tetra-hidro-[1,2']-bipirazinil-4-il)-metanona 5'-trifluorometil-3,4,5,6-te-tra-hidro-2H-[1,2']-bipirazinilo (composto 7.7) e ácido 5-iaetano-sulfonil-2-((R)-2,2,2-trifluoro-l-etil-etoxi)-benzóico (composto 5.7) 527,2 654 (2-isopropoxi-5-metano- 5'-trifluorometil-3,4,5,6-te- 473,4 201 sulfonil-fenil)-(5'-trifluorometil-2,3,5, 6-tetra-hidro-[1,2']-bipirazinil-4-il)-metanona tra-hidro-2H-[1,2']-bipirazi-nilo (composto 7.7} e ácido 2-isopropoxi-5-metano-sulfonil-benzóico (composto 1.2) 655 [ 5-metano-sulf oni1-2-me t il-etoxi)-fenil]-[4-(6-trifluorometil-piridazin-3-il)-piperazin-l-il]-metanona 3-piperazin-l-il-6-trifluorometil-piridazina (composto 7.8) e ácido 5-metano-sulfonil-2-((S)-2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 5.6) 527,3 656 (2-isopropoxi-5-fenil)-[4-(6-trifluorometil-piridazin-3-il)-piperazin-l-il)-metanona 3-piperazin-l-il-6-trifluorometil-piridazina (composto 7.8) e ácido 2-isopropoxi-5-metano-sulfoni1-benzóico (composto 1.2) 473,3 65*7 [5-metano-sulfonil-2-{(R)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(6-trifluorometil-piridazin-3-il)-piperazin-l-il]-metanona 3-piperazin-l-il-6-trifluorometil-piridazina (composto 7.8) e ácido 5-metano-sulfonil-2-((R)-2,2,2-trifluoro-1-metil-etoxi)-benzóico (composto 5.7) 527,3 658 ' [5-mstano-sulfonil-2-(2,2,2-trifluoro-1, 1-dimetil-etoxi)-fenil]-[4-(2-trifluorometil-pirimidin-5-il)-piperazin-l-il]-metanona 5-piperazin-l-il-2-trifluorometil-pirimidina (composto 7.6) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-benzóico (composto 7.2) 541,3 659 [5-metano-sulfonil-2-(2,2,2-trifluoro-1,1-dimetil-etoxi)-fenil]-[4-(6-trifluorometil-piridazin-3-il)-piperazin-l-il]-metanona 3-piperazin-l-il-6-trifluõrometil-piridazina (composto 7.8) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l, 1-dimetil-etoxi)-benzóico (composto 7.2) 541,3 660 [5-metano-sulfonil-2-(2,2,2-trifluoro-l,l-dimetil-etoxi)-fenil]-(5'-trifluorometil-2,3, 5, 6- tetra-hidro-[l,2']- bipirazinil-4-il)-metanona 5'-trifluorometil-3,4,5,6-tetra-hidro-2H-[1,2']-bipirazinilo (composto 7.7) e ácido 5-metano-sulfonil-2-(2,2,2-trifluoro-l,1— dimetil-etoxi)-benzóico (composto 7.2) 541,3Exemp. No. Systematic Name Initial Materials PM found. (M + H) 649 [5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - (4- (2-trifluoromethyl-pyrimidine 5-yl) -piperazin-1-yl] -methane-5-piperazin-1-yl-2-trifluoromethyl-pyrimidine (compound 7.6) and 5-methanesulfonyl-2 - ((S) (R) -2,2,2-trifluoro-1- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.6) methyl-ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyrimidin-5-yl) -piperazin-1-yl] -methanone 5-Piperazin-1-yl-2-trifluoromethyl-pyrimidine (compound 7.6) and 5-methanesulfonyl-2 - {(R) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid. (compound 5.7) 527.0 651 (2-isopropoxy-5-methanesulfonyl-phenyl) - [4- (2-trifluoromethyl-pyrimidin-5-yl) -piperazin-1-yl] -methanone 5-piperazin. yl-2-trifluoromethyl-pyrimidine (compound 7.6) and 2-isopropoxy-5-methanesulfonyl-beozoic acid (compound 1.2) 473.0 652. [5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - (5'-trifluoromethyl-2,3,5,6-tetrahydro- - [1,2 '] bipyrazinyl-4-yl) -methanone 5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyrazinyl (compound 7.7) and acid. 5-methanesulfonyl-2 - ((S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.6) -2,2-trifluoro-1-methyl-ethoxy) -phenyl] - (5'-trifluoromethyl-2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone 5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyrazinyl (compound 7.7) and 5-methanesulfonyl-2 - ((R) - 2,2,2-trifluoro-1-ethyl-ethoxy) -benzoic acid (compound 5.7) 527.2654 (2-isopropoxy-5-methano-5'-trifluoromethyl-3,4,5,6- 4,20-sulfonyl-phenyl) - (5'-trifluoromethyl-2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone-tetrahydro-2H- [1,2 (5-methanesulfonyl-2-methyl-ethoxy) -phenyl] - [4] -bipyrazine-2-carboxylic acid (compound 7.7) and 2-isopropoxy-5-methanesulfonyl- - (6-trifluoromethyl-pyridazin-3-yl) -piperazin-1-yl] -methanone 3-piperazin-1-yl-6-trifluoromethyl-pyridazine (compound 7.8) and 5-methanesulfonyl- S) -2,2,2-trifluoro-1-methyl-ethoxy) -benzoic acid (compound 5.6) 527.3 656 (2-isopropoxy-5-phenyl) - [4- (6-trifluoromethyl-pyrid 3-piperazin-1-yl-6-trifluoromethyl-pyridazine (compound 7.8) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2) , 3β, 7α-5-methanesulfonyl-2 - {(R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridazin-3-yl ) -piperazin-1-yl] -methanone 3-piperazin-1-yl-6-trifluoromethyl-pyridazine (compound 7.8) and 5-methanesulfonyl-2 - ((R) -2,2,2- 1-methyl-ethoxy) -benzoic acid (compound 5.7) 527.3 658 '[5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] - [4- (2-trifluoromethyl-pyrimidin-5-yl) -piperazin-1-yl] -methanone 5-piperazin-1-yl-2-trifluoromethyl-pyrimidine (compound 7.6) and 5-methanesulfonyl- 2,2-trifluoro-1,1-dimethyl-ethoxy) -benzoic acid (compound 7.2) 541.3 659 [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridazin-3-yl) -piperazin-1-yl] -methanone 3-piperazin-1-yl-6-trifluoromethyl-pyridazine (compound 7.8) and 5- sulfonyl-2- (2,2,2-trifluoro-1,1-dimethyl-ethoxy ) -benzoic acid (compound 7.2) 541.3 660 [5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethylethoxy) -phenyl] - (5'-trifluoromethyl-2,3 , 5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone 5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2'] - bipyrazinyl chloride (compound 7.7) and 5-methanesulfonyl-2- (2,2,2-trifluoro-1,1-dimethylethoxy) benzoic acid (compound 7.2) 541.3

Os compostos de fórmula geral I e os seus sais de adição utilizáveis sob . o ponto de vista farmacêutico, possuem propriedades farmacológicas valiosas. Especifica- 202 mente verificou-se que os compostos da presente invenção são bons inibidores do transportador I de glicina (TGli-1).The compounds of formula I and their addition salts usable under. the pharmacological point of view, have valuable pharmacological properties. The compounds of the present invention have been found to be good inhibitors of glycine transporter I (TGli-1).

Analisaram-se os compostos de acordo com o ensaio que se dá aqui a seguir.Compounds were analyzed according to the assay given hereinafter.

Soluções e materiaisSolutions and materials

Meio DMEM completo: Mistura nutriente F-12 (Gibco Life-technologies), soro bovino fetal (SBF) a 5 % (Gibco Life-technologies), penicilina/estreptomicina a 1 % (Gibco Life-technologies), 0,6 mg/mL de higromicina (Gibco Life-technologies) , glutamina 1 mM (Gibco Life-technologies).Complete DMEM medium: F-12 nutrient mixture (Gibco Life-technologies), 5% fetal bovine serum (SBF) (Gibco Life-technologies), 1% penicillin / streptomycin (Gibco Life technologies), 0.6 mg / ml hygromycin (Gibco Life-technologies), 1 mM glutamine (Gibco Life-technologies).

Tampão de absorção (TA) : NaCl 150 mM, Hepes-Tris 10 mM, pH 7,4, CaCl2 1 mM, KC1 2,5 mM, MgS04 2,5 mM, ( + )D-glícose 10 mM. Células Flp-in™-0HC. (Invitrogen Cat n°. R758-07) transfectadas estavelmente com ADNc de TGlim-lb.Absorption Buffer (TA): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl2, 2.5 mM KCl, 2.5 mM MgSO4, 10 mM (+) D-glycoside. Flp-in ™ -0HC cells. (Invitrogen Cat # R758-07) stably transfected with TGlim-1b cDNA.

Ensaio de inibição da absorção de glicina (TGlim-lb)Inhibition of glycine uptake test (TGlim-1b)

No primeiro dia, colocou-se me placa células de mamífero (Flp-in™-0HC) , transf ectadas com ADNc de TGlim-lb, a uma densidade de 40.000 células/tubo, em meio F-12 completo, .sem higromicina, em placas de cultura de 96 cavidades. No segundo dia, aspirou-se o meio e lavaram-se as células duas vezes com tampão de absorção (TA) . Incubaram-se então as células durante 20 minutos, a 22 °C, quer com (i) sem concorrente potencial, (ii) glicina 10 mM não radioactiva, (iii) uma concentração de um inibidor potencial. Utilizou-se uma gama de concentrações do inibidor potencial para gerar dados, para calcular a concentração de inibidor, que resultasse num efeito de 50 % (por exemplo CI50, a concentração do concorrente de inibição 203 da absorção de glicina em 5 0, %) . Adicionou-se então., imediatamente, uma solução contendo [3H]-glicina 60 nM (11— 16 Ci/mmole) e glicina não radioactiva 25 μΜ. Incubaram-se as placas com 'uma ligeira agitação e parou-se a reacção por aspiração da mistura e lavagem (3 vezes) com TA arrefecido com gelo. Fez-se a lise das células com um líquido de cintilação, agitou-se 3 horas e contou-se a ràdioactividade nas células utilizando um contador de cintilação.On the first day, mammalian cells (Flp-in ™ -0HC), transfected with TGlim-1b cDNA, were plated at a density of 40,000 cells / well in complete F-12 medium, without hygromycin, in 96-well culture dishes. On the second day, the medium was aspirated and the cells were washed twice with absorption buffer (TA). The cells were then incubated for 20 minutes at 22øC either with (i) no potential competitor, (ii) non-radioactive 10 mM glycine, (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor to generate data was calculated to calculate the inhibitor concentration, which resulted in a 50% effect (for example IC50, the concentration of the inhibitor 203 inhibitor of glycine uptake in 50%) . A solution containing 60 nM [3 H] -glycine (11-16 Ci / mmole) and 25 μ não non-radioactive glycine was then immediately added. The plates were incubated with gentle shaking and the reaction was quenched by aspiration of the mixture and washing (3 times) with ice-cold RT. Cells were lysed with scintillation liquid, shaken for 3 hours, and the radioactivity in the cells counted using a scintillation counter.

Os compostos preparados exibiram uma CI50 (μΜ) rio TGli-1, num intervalo de 0,006-5,0. Os compostos preferidos mostraram uma CI50 (μΜ) em TGLi-1, no intervalo de 0,006-0,05, conforme sem ostra no quadro a seguir.The prepared compounds exhibited an IC 50 (μΜ) TGli-1 river, in a range of 0.006-5.0. Preferred compounds showed an IC50 (μ) in TGLi-1, in the range of 0.006-0.05, according to no oyster in the table below.

Exemplo N°. CI50 (pM) Exemplo N° . CI50 (pM) Exemplo N° . CI50 (pM) 1 0,039 213 0,021 430 0, 037 5 0,012 215 0,049 435 0, 029 15 0,015 228 ' 0,047 437 0,026 28 0,012 234 0,043 438 0,047 54 0,05 244 0,042 . 439 0,021 62 : 0,017 247 ' 0, 03 ' 459 ' 0,04 63 0,028 249 0,032 · .4 61 0,046 64 0,025 250 0,061 464 0,02 66 0,032 251 0,032 465 0,04 68 0,008 256 0,032 466 0,026 70 0,008 258 0,086 468 ' 0,02 71 0,008 260 0,043 469 CM O , O i 1 72 0,026 261 0,043 470 0,03 . 74 0,016 2 62' . 0,042 475 0,04 78 0,012 281. 0,021 481 0,03 80 0,029 282 0,027 488 0,039 84 0,04 283 0,008 491 0,037 88 0,007 284 0,01 494 0,03 204Example No. IC 50 (wt). IC 50 (wt). IC50 (pM) 1 0.039 213 0.021 430 0.0377 0.012 215 0.049 435 0.029 15 0.015 228 0.047 437 0.026 28 0.012 234 0.043 438 0.047 54 0.05 244 0.042. 439 0.021 62: 0.017 247'0.03 '459' 0.04 63 0.028 249 0.032 · .4 61 0.046 64 0.025 250 0.061 464 0.02 66 0.032 251 0.032 465 0.04 68 0.008 256 0.032 466 0.026 70 0.008 258 0.086 468 '0.02 71 0.008 260 0.043 469 CM 0.027 0.026 261 0.043 470 0.03. 74 0.016 2 62 '. 0.042 475 0.04 78 0.012 281. 0.021 481 0.03 80 0.029 282 0.027 488 0.039 84 0.04 283 0.008 491 0.037 88 0.007 284 0.01 494 0.03 204

Exemplo N° . CIE0 (pM) Exemplo N° . CISo (pM) Exemplo N°. CI50 (pM) . 92 0,05 285 0,042 504 0,025 95 ' 0,035 287 0,033 505 0,024 100 0,02 288 0,025 506 0,046 104 0,046 289 0,018 ; 507 0,031 . 105 0,039 290 0,017 408 0,026 109 0,021 291 0,013 509 0,03 . 111 0,035 292 0,021 510 0,015 112 0,024 293 0,034 514 0, 045 116 0,019 294 0,037 515 0,04 117 0,044 295 0,016 517 0, 035 118 0,024 296 0,043 518 0, 033 128 0,02 . 298 0,021 519 0, 035 131 0,03 299 0,044 524 0, 012 132 0,038 300 0,016 525 0,021 135 0, 041 301 m 0 O 526 0,009 136 0,027 . 302 . 0,013 527 0,006 137 0,027 303 0,006 528 0, 015 138 0,017 311 0,04 5 529 0, 013 139 0,024 313 0,018 530 0,0057 142 0,034 317 0,04.1 531 0,028 144 0,045 319' 0,031 534 0,049 145 0,015 321 0,018 537 0,03 146 0,019 322 0,028 546 0,035 147 0, 031 324 0,039 554 0,019 148 0,036 325 0,033 557 0,042 164 0,019 328 0,032 558 0,029. . 165 0, 47 329 0,016 561 0,038 167 . 0,016 330 0,018 562 0,044 169 0,012 363 0,008 563 0,043 170 0,031 3 67 0,036 564 0, 041 172 0, 019 369 0,032 566 cn 0 0 205Example No. CIE0 (pM). CISo (pM). IC50 (pM). 92 0.05 285 0.042 504 0.025 95 '0.035 287 0.033 505 0.024 100 0.02 288 0.025 506 0.046 104 0.046 289 0.018; 507.031. 105 0.039 290 0.017 408 0.026 109 0.021 291 0.013 509 0.03. 111 0.035 292 0.021 510 0.015 112 0.024 293 0.034 514 0, 045 116 0.019 294 0.037 515 0.04 117 0.044 295 0.016 517 0, 035 118 0.024 296 0.043 518 0.033 128 0.02. 298 0.021 519 0, 035 131 0.03 299 0.044 524 0, 012 132 0.038 300 0.016 525 0.021 135 0, 041 301 m 0 0 526 0.009 136 0.027. 302. 0.013 527 0.006 137 0.027 303 0.006 528 0, 015 138 0.017 311 0.04 5 529 0, 013 139 0.024 313 0.018 530 0.0057 142 0.034 317 0.04.1 531 0.028 144 0.045 319 '0.031 534 0.049 145 0.015 321 0.018 537 0.03 146 0.019 322 0.028 546 0.035 147 0, 031 324 0.039 554 0.019 148 0.036 325 0.033 557 0.042 164 0.019 328 0.032 558 0.029. . 165 0.47 329 0.016 561 0.038 167. 0.016 330 0.018 562 0.044 169 0.012 363 0.008 563 0.043 170 0.031 3 67 0.036 564 0, 041 172 0, 019 369 0.032 566 cn 0 0 205

Exemplo N° . CIS0 &lt;pM) Exemplo N° . CI50 (pM) Exemplo N° . CI50 (pM) 180 0,036 371 0,041 . 568 0,044 182 ' 0,03 372 0,006 570 0,046 184 0,022· 373 · 0,035 571 0,05 186 . 0,048 375 0,035 573 0,037 194 0,047 393 0,032 574 0,034 196- 0,041 400 0,023 576 0,039 202 0,024 '407 0,027 578 0,041 207 0,023 408 0, 037 589 0,032 209 0,041 411 0,045 595 0,049 210 0,039 412 0, 033 637 0,047 211 0,043 413 0, 03 212 0,029 417 0,046Example No. CIS0 &lt; pM). IC 50 (wt). CI 50 (pM) 180 0.036 371 0.041. 568 0.044 182 '0.03 372 0.006 570 0.046 184 0.022 · 373 · 0.035 571 0.05 186. 0.048 375 0.035 573 0.037 194 0.047 393 0.032 574 0.034 196- 0.041 400 0.023 576 0.039 202 0.024 '407 0.027 578 0.041 207 0.023 408 0, 037 589 0.032 209 0.041 411 0.045 595 0.049 210 0.039 412 0, 033 637 0.047 211 0.043 413 0, 03 212 0.029 417 0.046

Os compostos de fórmula geral I e os sais aceitáveis sob o ponto de vista farmacêutico dos compostos de fórmula geral I, podem ser utilizados como medicamentos, por exemplo, sob a forma de preparações farmacêuticas. As preparações farmacêuticas podem ser administradas oralmente, por exemplo,' sob a forma de comprimidos, comprimidos revestidos, drageias, cápsulas de gelatina dura e mole, soluções, emulsões ou suspensões. A administração pode contudo ser efectuada rectalmente, por exemplo, sob a forma de supositórios, parentericamente, por exemplo, sob a forma de soluções de injecção.The compounds of Formula I and the pharmaceutically acceptable salts of the compounds of Formula I may be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Administration can, however, be effected rectally, for example, in the form of suppositories, parenterally, for example in the form of injection solutions.

Os compostos de fórmula geral I podem ser tratados com veículos inorgânicos ou orgânicos, inertes sob o ponto de vista farmacêutico, para a. produção de preparações farmacêuticas. Pode-se utilizar lactose, amido de milho ou os seus derivados, talco, ácido esteárico ou os seus sais e similares, por exemplo, como esses veículos, para comprimidos, comprimidos revestidos, drageias e cápsulas de gelati- 206 na dura. Os veículos apropriados para as cápsulas de gelatina mole são, por exemplo, óleos vegetais, ceras, gorduras, polióis semi-sólidos. e líquidos e similares. Consoante a natureza da substância activa não são necessários veículos, contudo, eles são normalmente necessários no caso das cápsulas de gelatina mole. Os veículos apropriados para a produção de soluções e de xaropes são, por exemplo, água, polióis, glicerol, óleos vegetais e similares. Os veículos apropriados para supositórios são, por exemplo, óleos naturais ou endurecidos, ceras, gorduras, polióis semi-líquidos ou líquidos e similares.The compounds of Formula I may be treated with pharmaceutically inert, inorganic or organic carriers for production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like may be used, for example, as such, for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for the soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid polyols. and liquids and the like. Depending on the nature of the active substance, no vehicles are required, however, they are normally required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

As preparações farmacêuticas podem, além disso, conter conservantes, solubilizantes, estabilizantes, agentes de molhagem, emulsionantes, adoçantes, corantes, aromatizan-tes, sais para fazer variar a pressão osmótica, tampões, agentes de alteração do sabor ou anti-oxidantes. Podem também conter ainda outras substâncias válidas sob o ponto de vista terapêutico.The pharmaceutical preparations may furthermore contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, taste altering agents or anti-oxidants. They may also contain other therapeutically valid substances.

Os medicamentos que contêm um composto de fórmula geral I ou um seu sal aceitável sob o ponto de vista farmacêutico e um veículo inerte sob o ponto de vista terapêutico, podem também constituir um dos objectos da presente invenção, assim como, acontece com o processo para a sua produção, que compreende em pôr em contacto um ou mais compostos de fórmula geral I e/ou sais de adição de ácido aceitáveis sob o ponto de vista farmacêutico e, se desejado, uma ou mais de outras substâncias válidas sob o ponto de vista terapêutico, numa forma de administração. galénica em conjunto com um ou mais veículos inertes sob o ponto de vista terapêutico. 207Medicaments containing a compound of Formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier may also be one of the objects of the present invention, as is the case with the process for the production thereof which comprises contacting one or more compounds of formula I and / or pharmaceutically acceptable acid addition salts and, if desired, one or more other substances valid from the point of view therapeutic use, in a form of administration. in combination with one or more therapeutically inert carriers. 207

As indicações mais preferidas de acordo com a presente invenção são aquelas que incluem distúrbios do sistema nervoso central, por exemplo, o tratamento ou a prevenção de esquizofrenia, distúrbios cognitivos e doença de Alzheimer. A dosagem pode variar dentro de amplos limites e terá que ser obviamente ajustada às necessidades individuais em cada caso em particular. No caso de administração oral, a dosagem para adultos pode variar desde cerca de 0,01 mg até cerca de 1.000 mg por dia de um composto de fórmula geral I ou de uma quantidade correspondente de um seu sal aceitável sob o ponto de vista farmacêutico. A dosagem diária pode ser administrada como uma dose única ou em doses divididas e, além disso, o limite superior pode também ser excedido quando isso se considerar indicado·.More preferred indications in accordance with the present invention are those including central nervous system disorders, for example, the treatment or prevention of schizophrenia, cognitive disorders and Alzheimer's disease. The dosage may vary within wide limits and will obviously have to be tailored to the individual needs in each particular case. In the case of oral administration, the dosage for adults may range from about 0.01 mg to about 1000 mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as a single dose or in divided doses and, in addition, the upper limit may also be exceeded where this is indicated.

Formulação de Comprimidos (Granulação em via Húmida)Tablet Formulation (Wet Granulation)

Item Ingredientes mg/compriraido 1. Composto de Fórm. Geral I 5 mg 5 25 mg 25 100 mg 100 500 mg 500 2. Lactose Anidra DTG 125 105 30 150 3. Sta-RX .1500 6 6 6 30 4 . Celulose Microcristalina 30 30 30 150 5. Estearato de Magnésio 1 1 1 1 Total 167 167 167 831Item Ingredients mg / tablet 1. Compound of Formula General I 5 mg 5 25 mg 25 100 mg 100 500 mg 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-RX .1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Processo de Fabrico 1. Misturar os items 1, 2, 3 e 4 e granulá-los com água purificada. 2. Secar os grânulos a 50 °C. 3. Passar os grânulos através de um equipamento de moagem apropriado. 208 4.Manufacturing Process 1. Mix items 1, 2, 3 and 4 and granulate them with purified water. 2. Dry the granules at 50 ° C. 3. Pass the granules through appropriate milling equipment. 208 4.

Adicionar o item 5 e misturar durante três minutos; comprimir numa prensa apropriada.Add item 5 and mix for three minutes; compress into an appropriate press.

Formulação de CápsulasCapsule Formulation

Item Ingredientes mg/cápsula 1. Composto de Fórm. Geral I 5 mg 5 25 mg 25 100 mg 100 500 mg 500 2. Lactose Hidratada 159 123 148 — 3. Amido de Milho 25 35 40 70 4. Talco 10 15 10 25 5. Estearato de Magnésio 1 2 2 . 5 Total 200 200 300 . 600Item Ingredients mg / capsule 1. Compound of Formula General I 5 mg 5 25 mg 25 100 mg 100 500 mg 500 2. Lactose Hydrate 159 123 148 - 3. Corn starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium stearate 1 2 2. 5 Total 200 200 300. 600

Processo de Fabrico 1. Misturar os itens 1, 2 e 3 num misturar apropriado, durante 30 minutos. 2. Adicionar os itens 4 e 5 e misturar durante .3 minutos. 3. Encher numa cápsula apropriada.Manufacturing Procedure 1. Mix items 1, 2 and 3 in an appropriate blender for 30 minutes. 2. Add items 4 and 5 and mix for .3 minutes. 3. Fill in a suitable capsule.

Lisboa, 25 de Fevereiro de 2008 209Lisbon, February 25, 2008

Claims (21)

REIVINDICAÇÕES Compostos de fórmula geralCompounds of general formula caracterizados pelo facto de Ar representar arilo insubstituido ou substituído seleccionado no grupo que consiste em fenilo, benzilo, naftilo, bifenilo e indanilo ou heteroariló com 6 átomos no núcleo, contendo um, dois ou três átomos' de. azoto e em. que os grupos arilo e heteroarilopodem estar substituídos por um ou mais substituintes seleccionados do grupo que consiste em hidrogénio, halogéneo, NO2, CN, alquilo Cx-Cg, alquilo Cx~Cg substituído .por halogéneo, alquilo'. Cx-Cg substituído por hidroxi, (CH2).n-alcoxi Cx-Cg, alcoxi Cx-Cg substituído por halogéneo, NR7R8, . C (0) R9, SO2R10, -C(CH3)=NOR7 ou por um heterociclo aromático com 5 átomos no núcleo contendo 1-4 heteroátomos, seleccionados entre N e 0, que está eventualmente substituído por alquilo Cx~C6; R1 representar hidrogénio ou alquilo Cx-Cg;' R2 representar hidrogénio ou alquilo Cx-C6, alcenilo C2-C6, alquilo Ci-Cs substituído por halogéneo, alquilo Ci~C6 substituído pòr hidroxi, (CH2)n-cicloalquilo C3-C7 eventualmente substituído por 1 alcoxi Cx-Cs ou por halogéneo ou representar CH (CH3) -cicloalquilo C3-C7, (CH2) n+i“C (0) R9, (CH2)n+i-CN, bibiclo [2.2.1] -heptilo, - (CH2)n+i-O-alquilo Ci-Cg, (CH2) n-heterocicloalquilof '' CCH2)n“ arilo ou (CH2) n-heteroarilo com 5 ou 6 átomos no núcleo contendo um, dois ou três heteroátomos selecciónados no grupo que consiste em oxigénio, enxofre ou azoto em que arilo, heterocicloalquilo e heteroarilo estão insubstituidos ou substituídos por um ou mais substituintes seleccionados no grupo que' consiste em hidroxi, halogéneo, alquilo Ci-Cg ou alcoxi Ci-Cg; R3, R4 e R6 representarem, independentemente uns dos outros, hidrogénio, hidroxi, halogéneo, alquilo Gi-C6 ou alcoxi Ci-C5 ou Ó-cicloalquilo C3-C6,· R5 representar N02, CN, C(0)R9 ou S02R10; R7 e R0 representarem, independentemente um do outro, hidrogénio ou alquilo Ci-C6; R9 representar hidrogénio, alquilo Ci-Cô, alcoxi Ci-C6 ou NR7R8; R10 representar alquilo C1-C6 eventualmente substituído por halogéneo, (CH2)n“CÍcloalquilo C3-C6, (CH2)n_ alcoxi C3-C6, (CH2) n-heterocicloalquilo ou NR7R8; n representar 0, 1, ou 2; e os seus sais de adição de acido aceitáveis sob o ponto de vista farmacêutico, 2 com a condição de que 1—[5-(amino-sulfonil)-2-metoxibenzoil]-4-(3-clorofe-nil)-piperazina, 1- [5- (amino-sulfonil) -2-metoxibenzoil] -4- (4-f.luoro-, fenil)-piperazina, 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-[3-(trifluo-rometil)fenil]-piperazina, 4-(3-amino-4-nitrofenil)-1-[4-(dimetilamino)-2-me-toxi-5-nitrobenzoil] -2-metilpiperazina, 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-4-(4-nitrofenil)-piperazina, 4- [4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-l-(4-nitrofenil)-piperazina, 1-(2-cloro-4-nitrofenil)-4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-piperazina, 1- [4- (dimetilamino) -2-metoxi-5-nitrobenzo.il] -4- (2, 4-dinitrofenil)-2-metil-piperazina, 1- (4-cloro-2-nitrofenil) -4-.[4- (dimetilamino) -2-metoxi- 5- nitrobenzoil]-piperazina 4 —[4 —(dimetilamino)-2-metoxi-5-nitrobenzoil]-1-(2,4-dinitrofenil)-2-metil-piperazina e 1-[(2-benziloxi-5-formil)benzoil]-4-fenilpiperazina estejam excluídos.characterized in that Ar is unsubstituted or substituted aryl selected from the group consisting of phenyl, benzyl, naphthyl, biphenyl and indanyl or 6-membered heteroaryl containing one, two or three carbon atoms. nitrogen and in. that the aryl and heteroaryl groups may be substituted by one or more substituents selected from the group consisting of hydrogen, halogen, NO 2, CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, Cx-Cg substituted by hydroxy, (CH2) n-C1-6 alkoxy, halogen substituted C1-6 alkoxy, NR7 R8,. C (O) R 9, SO 2 R 10, -C (CH 3) = NOR 7 or by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by C 1 -C 6 alkyl; R 1 is hydrogen or C 1 -C 6 alkyl; R 2 is hydrogen or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl substituted by halogen, C 1 -C 6 alkyl substituted by hydroxy, (CH 2) n -C 3 -C 7 cycloalkyl optionally substituted by 1 -C 1 -C 6 alkoxy or by halogen or (CH 2) n + i-CN, bibicyclo [2.2.1] heptyl, - (CH 2) n + iO (C 1 -C 6) alkyl, (CH 2) n-heterocycloalkyl, or (CCH 2) n aryl or (CH 2) n-heteroaryl having 5 or 6 ring atoms containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen in which aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C1 -C6 alkyl or C1 -C6 alkoxy; R 3, R 4 and R 6 are each independently hydrogen, hydroxy, halogen, C 1 -C 6 alkyl or C 1 -C 5 alkoxy or C 3 -C 6 -cycloalkyl, R 5 is NO 2, CN, C (O) R 9 or SO 2 R 10; R7 and R0 are independently hydrogen or C1 -C6 alkyl; R9 is hydrogen, C1 -C6 alkyl, C1 -C6 alkoxy or NR7 R8; R 10 represents C 1 -C 6 alkyl optionally substituted by halogen, (CH 2) n C 3 -C 6 cycloalkyl, (CH 2) n C 3 -C 6 alkoxy, (CH 2) n -heterocycloalkyl or NR 7 R 8; n is 0, 1, or 2; and the pharmaceutically acceptable acid addition salts thereof, with the proviso that 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chloro-phenyl) -piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (4-fluoro-, phenyl) -piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- [ 3- (trifluoromethyl) phenyl] piperazine, 4- (3-amino-4-nitrophenyl) -1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methylpiperazine, 1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl-4- (4-nitrophenyl) piperazine, 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2- methyl-1- (4-nitrophenyl) piperazine, 1- (2-chloro-4-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] piperazine, 1- [4- dimethylamino) -2-methoxy-5-nitrobenzoyl] -4- (2,4-dinitrophenyl) -2-methylpiperazine, 1- (4-chloro-2-nitrophenyl) -4- [4- (dimethylamino ) -2- methoxy-5-nitrobenzoyl] -1- (2,4-dinitrophenyl) -2-methylpiperazine and 1 - [( 2-benzyloxy-5-formyl) benzoyl] -4 -phenylpiperazine are excluded. 2. Composto de fórmula I, de acordo com a reivindicação 1, caracterizados pelo facto de Ar representar fenilo substituído, R2 representa alquilo Ci-Cg e R5 representar S(0)2CH3 ou S(0}2CH2CH3·.A compound of formula I according to claim 1, wherein Ar is substituted phenyl, R 2 is C 1 -C 6 alkyl and R 5 is S (O) 2 CH 3 or S (O) 2 CH 2 CH 3. 3. Compostos de fórmula I, de acordo com a reivindicação 2, caracterizados pelo facto de representarem: 3 1- {3-fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, 3- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 2- Fluoro-4-[4-(2-isopropoxi-5-metanò-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo&gt; [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanona, l-{3-fluoro-4-[4-(2-isobutoxi-5-metanó-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, 4- [4-(2-isobutoxi-5-metano-sulfonil-bénzoil)-piperazin- 1- il]-benzonitrilo, 3- fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 2- fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metil-fen.il)-piperazin-l-il]-metanona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil)-metanona, [4-(3-fluoro-4-trifluòrometil-fenil)-piperazin-l-il] -(2-isobutoxi-5-metano-sulfonil-fenil)-metanona, [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfoni.l-fenil) -metanona, [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-,(2-isopropoxi-5-metano-sulfonil-fenil)-metanona, 2.3- difluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 2.3- difluoro-4- [4- (2-isobutoxi-5-metano-s.ulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 2,5.-dif luoro-4- [4- (2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 2,6-difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 4 3,5-difluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo, 4- [4- (2-tert-butoxi-5-metano-sulfonil-benzoil) -pipe-razin-l-il]-2,3-difluoro-benzonitrilo, 5- clorò“2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzonitrilo, 4- [4- (2-terc-butoxi-5-metano-sulfonil“benzoIl) --piperazin-l-il] -2,5-difluoro-benzonitrilo, 4- [4- (.2-terc-butoxi-5-metano-sulfonil“benzoil) -pipera-zin-l-il]-3-fluoro-benzonitrilo, (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-terc-butoxi-5-metano-sulfonil-fenil)-[4-(2&gt;5-di-fluò-ro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona, 1-(4-{4-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-ben-zoil]-piperazin-l-il}-3-fluorofenil)-etanona, 4-{4-[2-(2,2-dimetil-propoxi)-S-metano-sulfonil-ben-zoil]-piperazin-l-il}-benzonitrilo, 4-{4-[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-ben-zoil]-piperazin-l-il}-3-fluoro-benzonitrilo, 4 — {4 —[2-(2,2-dimetil-propoxi)-5-metano-sulfonil-ben-zoil]-piperazin-1 -il}-2-fluoro-benzonitrilo, (2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]- [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-{2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-(2,2-dimetil-propoxi)-5-metano-sulfonil-fenil]-[4-(2-fluoro-4-ètano-sulfonil-fenil)-piperazin-l-il]-metanona, 5 rac-l-{4-[4- (2-sec-butoxi-5-metano-sulforiil-benzoil) -piperazin-1-il]-3-f luoro-f enil }.-etanona, rac-4-[4-(2-sec-butoxi-5-metano-sulfonil-benzoil·)-piperazin-l-il]-3-fluoro-berizonitrilo, rac-4-[4-(2-sec-butoxi-5-metano-sulfonil-benzoil) -piperazin-l-il] -2-fluoro-benzonitrilo, rac-(2-sec-butoxi-5-metano“Sulfonil-fenil)-[4-(2-fluo-ro-4-trifluorometil-fenil)-piperazin-l-il]-metanóna, rac-(2-sec-butoxi-5-metano-sulfonil-fenil)-(4-(3-fluo-ro-4-trifluorometil^fenil)-piperazin-l-il] -metanóna, (2-isopropoxi-5-metano-sulfonil-fenil)-[4-(4-trifluoro-metano-sulfonil-fenil)-piperazin-l-il]-metanóna, (2-isobutoxi-5-metano-sulfonil-fenil)-[4-(4-trifÍuoro-metano-sulfonil-fenil)-piperazin-l-il]-metanóna, . 2-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -5-trifluorometil-benzonitrilo, 1-{2-fluoro-4-[4-{2-isopropoxi-5-metano-sulfonil-ben- ‘ zoil)-piperazin-l-il]-fenil}-etanona,.Compounds of formula I according to claim 2, characterized in that they represent: 1- {3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazine yl] -phenyl} -ethanone, 3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2-Fluoro-4- [ 4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile &gt; [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 1- {3-fluoro-4- [4- (2-isobutoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -phenyl} -ethanone, 4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1 3-fluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2-fluoro-4- [4- (2- isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, (2-isobutoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethylphenyl) -piperazine (4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, [4- (2-fluoro- 3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, [4- (2-fluoro-4-methanesulfonyl- 1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -piperazin- , 2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 2,3-difluoro-4- [4- (2-isopropoxy-5- sulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2,3-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2,5-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 2,6-difluoro-4- [4- (2- isobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 3,5-difluoro-4- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) - piperazin-1-yl] benzonitrile, 4- [4- (2-tert-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluorobenzonitrile, 5-chloro 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (2- tert -butoxy-5-methanesulfonylbenzoyl) - piperazin-1-yl] -2,5-difluoro-benzonitrile, 4- [4- (2-tert-butoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -3-fluoro (2-tert-butoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 5-methanesulfonyl-phenyl) - [4- (2 &gt; 5-difluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl ] -methanone, 1- (4- {4- [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -3-fluorophenyl) -ethanone, 4- {4- [2- (2,2-dimethyl-propoxy) -S-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile, 4- {4- [2- (2,2- dimethylpropoxy) -5-methanesulfonylbenzoyl] piperazin-1-yl} -3-fluoro-benzonitrile, 4- {4- [2- (2,2-dimethyl-propoxy) -5- methanesulfonyl-benzoyl] -piperazin-1-yl} -2-fluoro-benzonitrile, (2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (4- trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-trifluoromethyl-phenyl) piperazin-1-yl] -methanone, (2- {2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1 -yl] -methanone, [2- (2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [4- (2-fluoro-4-ethanesulfonyl-phenyl) -piperazin- ] -methanone, 5 rac-1- {4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone, rac-4- [4- (2-sec-butoxy-5-methanesulfonyl- chloro-1-benzoyl) -piperazin-1-yl] -3-fluoro-berizonitrile, rac-4- [4- (2-sec-butoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2- (2-sec-butoxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, rac (2-sec-butoxy-5-methanesulfonyl-phenyl) - (4- (3-fluoro-4-trifluoromethylphenyl) -piperazin-1-yl] -methanone, (2-isopropoxy-5- methanesulfonyl-phenyl) - [4- (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone, (2-isobutoxy-5-methanesulfonyl-phenyl) - [4- (4- -trifluoro-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone. 2- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5-trifluoromethyl-benzonitrile, 1- {2-fluoro-4- [4- (2-isopropoxy-5- methanesulfonyl-benzoyl) -piperazin-1-yl] -phenyl} -ethanone. [4-(3-fluoro-4-metanes ulfonil-fenil)-piperazin-l-il]- (2-isobutoxi-5-metano-sulfonil-fenil)-metanóna, 1- {2-fluoro-4-[4-(2-isobutoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-fenil}-etanona, 2- [4-(2-isobutoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -5-trif luorometil-benzonitrilo, (5-etano-sulfonil-2-isopropoxi-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanóna, [4-(4-difluorometil-2-fluoro-fenil)-piperazin^l-il]-(2-isopropoxi-5-metano-sulfonil-fenil)-metanóna, [4-(3-cloro-5-trifluorometil-piridin-2-ilj-piperazin-l-il] - (2-isopropoxi-5-metano-sulfonil- fenil)-metanóna, 3- fluoro-4-[4-(2-isopropoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-benzaldeido, [4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-(2-isobutoxi-5-metano-sulfonil-fenil;) -metanóna, 6 rac-(2-sec-butoxi-5-metano-sulfonir-fenil)-[4-(4-eta-no-sulfonil-2-fluoro-feníl) -piperazin-l-il] -metano-na, [4-(4-ciclobutano-sulfonil-2-fluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil·)-metanona, [4- (4-ciclopentanesulfonil-2-fluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil)-metanona,' [4-(4'-ciclopropanO&quot;Sulfonil-2-fluoro-fenil) -piperazin-l-il] -(2-isobutoxi-5-metano-sulfoni-fenil)-metanona e [4-(4-ciclopropano-esulfonil-2,5-difluoro-fenil)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfoniÍ-fenil) -me- ' tanona. 4. Composto.s de fórmula .1, dê acordo com a- reivindicação 1, caracterizados pelo facto de Ar representar fenilo substituído, .R2 representar (CH2)n~cícloalquilo C3-C7 e R5 representar. S (0) 2CH3.[4- (3-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) -methanone, 1- {2-fluoro-4- [4- - (2-isobutoxy-5-methanesulfonylbenzoyl) -piperazin-1-yl] -phenyl} -ethanone, 2- [4- (2-isobutoxy-5-methanesulfonyl-benzoyl) -piperazin- yl] -5-trifluoromethyl-benzonitrile, (5-ethanesulfonyl-2-isopropoxy-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [4- (4-difluoromethyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, [4- (3-chloro-5-trifluoromethyl- pyridin-2-yl] -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, 3-fluoro-4- [4- (2-isopropoxy-5-methanesulfonylbenzoyl ) -piperazin-1-yl] -benzaldehyde, [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonyl-phenyl) methanesulfonic acid, 6-rac- (2-sec-butoxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone , [4- (4-cyclobutanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methane (4-cyclopentanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone, [4- - (4'-cyclopropane &quot; Sulphonyl-2-fluoro-phenyl) -piperazin-1-yl] - (2-isobutoxy-5-methanesulfonylphenyl) -methanone and [4- (4-cyclopropane-sulfonyl-2 , 5-difluoro-phenyl) -piperazin-1-yl] - (2-isopropoxy-5-methanesulfonyl-phenyl) -methanone. Compounds of formula .1, according to claim 1, wherein Ar is substituted phenyl, R2 represents (CH2) n -C3 -C7 cycloalkyl and R5 represents. S (O) 2 CH 3. 5. Compostos de fórmula I, de acordo com a reivindicação 4, caracterizados pelo facto de serem representados por: 1—{4—[4- (2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-fenil}-etanona, 4-[4-(2-Ciclopropilmetoxi-5-metano-sulfonil-benzoil)-pi-pefãzin-l-ii]-benzonitrilo, 4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-3-fluoro-benzonitrilo, 4-[4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo, {2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-[4-(4-tri-fluorometil-fenil)-piperazin-l-il]-metanona, (2-ciclopropilmetoxi-5-mètano-sulfonil-fenil)-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, 7 (2-ciclopropilmetoxi-5-metano-sulfónil-fenil)-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il] -metariona, 1 — {4 —[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -3-fluoro-fen.il }-étanona, : 4-(4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -benzoni-trilo, 4 - [4- (2-ciclopentiloxi-5-metano-sulfonil-berizoil) -piperazin-l-il] -3-fluoro-benzonitrilo, 4-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -2-fluoro-benzonitrilo, .(2-ciclopentiloxi-5-metano-sUlfonil-fenil)-[4- (2-fiuo-ro-4-trifluorom.etil-fenil)-piperazin-l-il]-metanona, (2 -ciclopentiloxi-5-metano-sulfonil-feni 1) - [ 4 - ( 3- f luoro-4-trifluorometil-fenil)-piperazin-l-il] -mer.anona, (2-cicÍopentiloxi-5-metano-sulfònil-f en.il) - [4 - (4-trifluo-ròmetil-fenil)-piperazin-l-il]-metanona, : Rac- [2- (l-ciclopropil-étoxi)'-5-metano-sulfonil-fenil] -[4-{4-trifluorometil-fenil)-pipérazin-l-il]-metanona, .4-[4-(2-cicÍopentiloxi-5-:m.etano-sulfonil-benzoiÍ)-piperazin-l-il] -2,3-difluorc-benzonitrilo, 4- [4-:(2-ciclop.entiloxi-5-metano-sulfonil-benzoil) -piperazin-l-il]-2, 5-difluoro-benzonitrilo, 4 - [4- ^-ciclobutilmetoxi-S-metano-sulfonil-benzoil)-pi-perazin-l-il]-benzonitrilo, 4-[4- (^-ciclobutilmetoxi-S-metano-sulfonil-benzoil)-piperazin-l-il]-2-fluoro-benzonitrilo, . 4-[4-(2-ciclQbutiÍmetoxi-5-metano“Sulfon±l-benzoil)-pi- perazin-l-il]-3-fluoro-benzonitrilo, (2-ciclòbutilmetoxi-5;-metano-sulfonil-fenil) - [4- (4-trifluorometil-fénil}-piperazin-l-il]-metanona, 1 — {4 —[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-piperazín-l-il]-3-fluoro-fenil}-etanona, 2- [4- (2-οίο1ο^ΐϊΐΓηβ^χί-5-π^3ηο-3α1.£οηϊ1^βηζο11) -pi-*pérazin-l-il]-5-trifÍuórometiÍ-benzonitrilo, 8 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-pi— perazin-l-il]-2,3-difluoro-benzonitrilo, 4-[4-(2-cíclobutilmetoxi-5-metano-sulfonil-benzoil)-pi-,perazin-l-il]-2,5-difluoro-benzonitrilo, ' 4-[4-(2-ciclobutilmetoxi-5-metano-surfonil-benzoil)-pi-perazin-l-il]-3,5-difluoro-benzonitrilo, 4-[4-(2-ciclobutilmetoxi-5-metano-sulfonil-benzoil)-pi-perazin-l-il]-2,6-difluoro-benzonitrilo, 4-[4-(2-ciclopropiÍm.etoxi-5-metano-sulf onil-benzoil)-pi-perazín-l-il]-3., 5-difluoro-benzonitrilo, 4- [4- (2-ciclopentiloxi-5-itietano-sulfonil-benzoil) -pipe-razin-l-il]-3,5-difluoro-benzonitrilo, 4- [4-(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-pi-perazin-l-il]-2,6-difluoro-benzonitrilo, 4 — [4 — (2-ciclopentiloxi-5-inetano-sulfonil-benzoil) -pipe-razin-l-il]-2,6-difluoro-benzonitrilo, 5- cloro-2-[4- (2-ciclopropilmetoxi-5-metano-sulfonil-ben-zoil)-piperazin-l-il]-benzonitrilo,: 4-[4-(2-ciclohexiloxi-5-metano-sulfonil-benzoil)-pipera-zin-l-il]-benzonitrilo, 4-.[4- (2-ciclohexiloxi-5“metano-sulfonil-benzoil·) -pipera-zin-l-il]-3-fluoro-benzonitrilo, 4-[4-{2-cicloh-exiloxi-5-metano-sulfonil-benzoil)-pipe-razin-l-il]-2-fluoro-benzonitrilo, (2-ciclo-hexiloxi—5-metano-sulfonil-fenil)- [4-(4-tri-fluorometil-fenil)-piperazin-l-il]-metanona, (.2-ciclo-hexiloxi-5^metano-sulfonil-fenil) - [4- (3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona,· (2-ciclO“&quot;hexiloxi-5-metano-sulfonil-f enil) - [4- (2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-metanona, l-{4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-pipe-razin-l-il]-3-fluoro-fenil}-etanona, 4-[4-(2-ciclobutoxi-5-metano-sulfonil-benzoil)-pipera-zin-l-il]-3-fluoro-benzonitrilo, 9 (2-ciclobutoxi-5-metano-sulfonil-fenil) - [.4- (3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2“CÍclopentiloxi-5-metano-sulfonil-fenil)-.[4-(4-tri— fluorometano-sulfonil-fenil)-piperazin-l-il]-metanona, 1— {4—[4—(2-ciclopropilmetoxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -2-fluoro-fenil}-etanona, 2- [4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)^pipe-razin-l-il]-5-trifluorometil-benzonitrilo, (2-ciclopropilnietoxi-5-itietano-sulfonil-fenil) - [4- (4-eta-no-sulfonil-2-fluoro-fenil·) -piperazin-l-il] -metanona, {2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(4-etano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclo-hexiloxi-5-metano-sulfonil-fenil)-[4-{4-eta-no-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil) -.[4- (4-ciclo-propano-sulfonil-2-fluoro-fenil)-piperazin-l-il-metaóo-na, (2-ciclo-hexiloxi-5-metano-esulfonil-fenil)-[4-(4-ci-clopropano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona, (2-ciclobutoxi-5-metano-sulfonil-fenil)-[4-(4-ciclo-propano-sulfonil-2-fluoro-fenil)-piperazin-l-il]-metanona .Compounds of formula I according to claim 4, characterized in that they are represented by: 1- {4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl} -ethanone, 4- [4- (2-Cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (2-cyclopropylmethoxy- 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2- fluoro-benzonitrile, (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclopropylmethoxy-5-methanesulfonyl -phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 7- (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro 1- (4- [4- (2-Cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-phenyl) -piperazin-1-yl] phenyl] -ethanone,: 4- (4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzo 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclopentyloxy-5- (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin- ) -piperazin-1-yl] -methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -mer (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, Rac- [2- (1-methanesulfonyl- 5-methanesulfonyl-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 4- [4- (2-cyclopentyloxy-5- benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile, 4- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1- yl] -2,5-difluorobenzonitrile, 4- [4- (Cyclobutylmethoxy-S-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile, 4- [4- (4-cyclobutylmethoxy- S-methanesulfonyl-benzoyl) -piperazin- 1-yl] -2-fluoro-benzonitrile. 4- [4- (2-Cyclobutylmethoxy-5-methano) sulfonylbenzoyl) piperazin-1-yl] -3-fluoro-benzonitrile, (2-Cyclobutylmethoxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin- 3-fluoro-phenyl} -ethanone, 2- [4- (2-chlorophenyl) -3- (3-chlorophenyl) -piperazin-1-yl] -5- 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,3-difluoro-benzonitrile, 4- [4- (2- 5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,5-difluorobenzonitrile, 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin yl] -3,5-difluorobenzonitrile, 4- [4- (2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile, 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3,5-difluoro-benzonitrile, 4- [4- (2-cyclopentyloxy- 5-ylethanesulfonyl-benzoyl) -pipe 4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile, benzonitrile, 4- [4- (2-cyclopentyloxy-5-inethanesulfonylbenzoyl) -piperazin-1-yl] -2,6-difluoro-benzonitrile, 5-chloro-2- [4- (2- cyclopropylmethoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -benzonitrile,: 4- [4- (2-cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] 4- [2- (cyclohexyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, 4- [4- (2-cyclohexyl) -5-methanesulfonyl-benzoyl) -piperazin-1-yl] -2-fluoro-benzonitrile, (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (4-trifluoromethyl) -phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl ] -methanone, · (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- (2-cyclobutoxy-5-methanesulfonyl-benzoyl) -piperazine ynyl] -3-fluoro-phenyl} -ethanone, 4- [4- (2-cyclobutoxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -3-fluoro-benzonitrile, (2-Cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2 "Cyclopentyloxy-5-methanesulfonyl -phenyl) - [4- (4-trifluoromethanesulfonyl-phenyl) -piperazin-1-yl] -methanone, 1- {4- [4- (2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl) piperazin-1-yl] -2-fluoro-phenyl} -ethanone, 2- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -5-trifluoromethyl-benzonitrile (2-cyclopropylmethoxy-5-methylsulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclopentyloxy-5- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy-5-methanesulfonyl-phenyl) - [4- (4-ethanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (4- propanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl-meta-2 (4-Cyclohexylsulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone, (2-cyclohexyloxy-5-methanesulfonyl- cyclobutoxy-5-methanesulfonyl-phenyl) - [4- (4-cyclopropanesulfonyl-2-fluoro-phenyl) -piperazin-1-yl] -methanone. 6. Compostos de fórmula I de acordo com a reivindicação 1, caractefizado pelo facto de Ar representar: fenilo substituído, R2 representar alquilo Ci-Cs substituído por halogéneo e R5 representar S(0)2CH3.Compounds of formula I according to claim 1, wherein Ar is: substituted phenyl, R 2 is C 1 -C 6 alkyl substituted by halogen and R 5 is S (O) 2 CH 3. 7. Compostos de- fórmula I de acordo com a reivindicação 6, caracterizados pelo facto de os compostos serem representados por: 10 1-(3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-benzoil]-piperazin-l-il]-fenil)-etanona, 3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi) -benzoil] -piperazin-l-il}-benzonitrilo, [4-(2-- fluoro-4-trifluorometil-fenil) -piperazin-l-il) -[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi}-fenil]-me-tanona, [4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-me-tanona, [4-(2-fluoro-4-metano-sulfonil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,2-trifluoro-etoxi)-fenil]-me-tanona, 3-fluoro-4-{4-[5“metano-sulfonil-2-(3,3,3-trirfluoro-propoxi)-benzoil)-piperazin-l-il}-benzonitrilo, [4-(3-fluoro-4-trifluororaetil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-fenil]-metanona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-fenil]-metanona, 1- (3-fluoro-4-{4-[5-metano-sulfonil-2-(3,3,3-trifluoro-propoxi)-benzoil]-piperazin-l-il}-fenil)-etanona, 2,5-difluoro-4-[4-(5-metano-sulfonil-2-trifluorometoxi-benzoil)-piperazin-l-il]-benzonitrilo, 2,3-difluoro-4-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5- metano-sulfo.nil-benzoil] -piperazin-l-il} -benzonitrilo, 2- fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-penta- fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, [5-metano-sulfonil-2-(2,2,3,3,3-pentafluoro-propoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-me-tanona, 11 2.3- difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-pen-tafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 3, 5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3,3-pen-tafluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitri-lo, 2-{4-[2-(2-fluoro-l-fluorometil-etoxi)-5-metano-sulfo-nil-benzoil]-piperazin-l-il}-5-trifluorometil-benzoni-trilo, rac-2,3-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri- . fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzo-nitrilo, 2- Fluoro-4-{4-[5-metano-sulfonil-2^(2,2,3,3-tetra- fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 3- fluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, [5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-fe-nll]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-meta-nona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-(2,2,3,3-tetrafluoro-propoxi)-fe-nil]-metanona, 2.3- difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 3,5-Difluoro-4-{4-[5-metano-sulfonil-2-(2,2,3,3-tetra-fluoro-propoxi)-benzoil]-piperazin-1 -il}-benzonitrilo, [4- ('3,4-dichloro-fenil) -piperazin-l-il] - [5-metano-sul-fonil-2-(2,2,2-trifluoro-etoxi)-fenil]-metanona, rac-5-cloro-2-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) -benzoil]-piperazin-l-il}-benzonitrilo, rac-3,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, 12 rac-2,5-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin~l-il}-benzo-nitrilo, rac-2,6-difluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-tri-fluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzoni-trilo, rac-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-benzoil]-piperazin-l-il}-benzonitrilo, rac-3-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-l-metil-etoxi}-benzoil]-piperazin-l-il}-benzonitri- 1c, rac-2-fluoro-4-{4-[5-metano-sulfonil-2-(2,2,2-trifluo-ro-l-metil-etoxi)-benzoil]-piperazin-l-il·}-benzonitri-i°, rac-5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi}-fenil]-[4-(4-trifluorometilfenil)-piperazin-l-il] -metanona, rac-[4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona, rac-[4-(3-fluoro-4-trifluorometil-fenil)-piperazin-l-il] -[5-metano-sulfonil-2- (2, 2,2-trifluoro-l-metil- . etoxi)-fenil]-metanona, [4-(2-fluoro-4-trifluorometil-fenil)-piperazin-l-il]-[5-metano-sulfonil-2-((S ou R)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-metanona, [5-metano-sulfonil-2-((S ou R)-2,2,2-trifluoro-l-metil-· etoxi) -fenil].- [4- (4-trifluorometilfenil) -piperazin-l- il]-metanona e [5-metano-sulfonil-2-((R ou S)-2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(4-trifluorometilfenil)-piperazin-1-. il]-metanona. 13Compounds of formula I according to claim 6, characterized in that the compounds are represented by: 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2- , 2-trifluoro-ethoxy) -benzoyl] -piperazin-1-yl] -phenyl) -ethanone, 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,2- ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl) - [5-methanesulfonyl- (4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,4- 2,2-trifluoro-ethoxy) -phenyl] -methanone, [4- (2-fluoro-4-methanesulfonyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- 2,2-trifluoro-ethoxy) -phenyl] -methanone, 3-fluoro-4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) benzoyl) (4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-trifluoro-phenyl) -piperazin-1-yl] -benzonitrile, propoxy) -phenyl] -methanone, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (3,3,3-tr trifluoro-propoxy) -phenyl] -methanone, 1- (3-fluoro-4- {4- [5-methanesulfonyl-2- (3,3,3-trifluoro-propoxy) -benzoyl] -piperazin- yl} -phenyl) -ethanone, 2,5-difluoro-4- [4- (5-methanesulfonyl-2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -benzonitrile, 2,3-difluoro- {4- [2- (2-fluoro-1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -benzonitrile, 2-fluoro-4- {4- [5- methanesulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, [5-methanesulfonyl-2- 3,3,3-pentafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 2,3-difluoro-4- {4- [5-methane 2-sulfonyl-2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 3,5-difluoro-4- {4- [5-methane 2- (2,2,3,3,3-pentafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 2- {4- [2- (2-fluoro- 1-fluoromethyl-ethoxy) -5-methanesulfonyl-benzoyl] -piperazin-1-yl} -5-trifluoromethyl-benzonitrile, rac-2,3-difluoro-4- {4- [5-methane sulfonyl-2- (2,2,2-tri- fluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 2-Fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3- tetrafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 3-fluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro- propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl) -phenyl) -piperazin-1-yl] -methanone, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- , 3,3-tetrafluoro-propoxy) -phenyl] -methanone, 2,3-difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, 3,5-Difluoro-4- {4- [5-methanesulfonyl-2- (2,2,3,3-tetrafluoro-propoxy) benzoyl] ] -piperazin-1-yl} -benzonitrile, [4- (3,4-dichloro-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-ethoxy) -phenyl] -methanone, rac-5-chloro-2- {4- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazine yl} benzonitrile, rac-3,5-difluoro-4- {4- [5-methanesulfonyl-2- (2,4- 2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-2,5-difluoro-4- {4- [5-methanesulfonyl- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-2,6-difluoro-4- {4- [5- sulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac 4- {4- [5-methanesulfonyl- 2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-3-fluoro-4- {4- [5-methanesulfonyl- (2,2,2-trifluoro-1-methyl-ethoxy} -benzoyl] -piperazin-1-yl} -benzonitrile, rac-2-fluoro-4- {4- [5-methanesulfonyl- 2- (2,2,2-trifluoro-1-methyl-ethoxy) -benzoyl] -piperazin-1-yl} -benzonitrile, rac-5-methanesulfonyl-2- , 2-trifluoro-1-methyl-ethoxy} -phenyl] - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone, rac- [4- (2-fluoro-4-trifluoromethyl- piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, rac- [4- (3-fluoro-4-trifluoromethyl -phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl- ethoxy) -phenyl] -methanone, [4- (2-fluoro-4-trifluoromethyl-phenyl) -piperazin-1-yl] - [5-methanesulfonyl-2 - ((S or R) 2-trifluoromethyl-1-methyl-ethoxy) -phenyl] -methanone, [5-methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro- - [4- (4-trifluoromethylphenyl) -piperazin-1-yl] -methanone and [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (4-trifluoromethylphenyl) -piperazin-1-one. yl] -methanone. 13 8. Compostos de fórmula I, de acordo com a reivindicação. 1, caracterizados pelo facto de Ar representar fenilo substituído, R2 representar alquilo Οχ-Οε; alquilo Οχ-Ce substituído por halogéneo, (CH2) n-cicloalquilo C3-C7, biciclo[2.2.1]heptilo, (CH2) n“0-al.quilo Ci-Cg ou (CH2)n“ heterocicloalquilo e R5 representar N02.Compounds of formula I according to claim 1. 1, wherein Ar is substituted phenyl, R 2 is alkyl χ-ε; (CH 2) n-C 3 -C 7 -cycloalkyl, bicyclo [2.2.1] heptyl, (CH 2) n -O-C 1 -C 6 alkyl or (CH 2) n -heterocycloalkyl and R 5 represents NO 2 . 9. Compostos de fórmula I, de acordo com a ..reivindicação 8, caracterizados pelo facto de esses compostos serem re-, presentados por 1-(3-fluoro-4-{4-[2-(2-metoxi-etoxi)-5-nitro-benzoil]— piperazin-l-il}-fenil)-etanona, (2“isopropoxi-5-nitro-fenil)-[4-(4-trifluorometii-fe-nil)-piperazin-l-il]-metanona,. :(2-ciclopropilmetoxi-5-nit.ro-fenil)-[4-(4-trifluorome-til-fenil)-piperazin-l-il]-metanona, (2-ciclobutilmetoxi-5-nitro-fenil)-[4-(4-trifluorome-. til-fenil)-piperazin-l-il]-metanona, (2-butoxi-5-nitro-fenil)-[4- [4-trifluorometil-fenil)-piperazin-l-il]-metanona, .[2-(2,2-dimetil-propoxi)-5-nitro-fenil]-[4-(4-trifluo-rometil-fenil)-piperazin-l-il]-metanona, (2-isobutoxi-5-nitro-fenil)-[4-(4-trifluorometil-fe-nil)-piperazin-l-il]-metanona, (2-ciclopentiloxi-5-nitro-fenil).- [4- (4-trifluorometil-. fenil)-piperazin-l-il]-metanona, (5-nitro-2-propoxi-fenil)-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, (2-ciclobutoxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il J -metanona, Rac-(2-sec-butoxi-5-nitro-fenil)-[4-(4-trifluorometil-fenil) -piperazin-l-il] -metanona, 14 [5-nitro-2- (2,.2^ 3, 3-tetrafluoro-propoxi) -fenil] - [4- (4-trifluorometil-fenil)-piperazin-l-il]-metanona, [5-nitro-2-(2,2,2-trifluoro-etoxi)-fenil]-[4-(4-tri-fluorome.til-fenil)-piperazin-l-il]-metanona, [2-(biciclo[2.2.1]hept-2-iloxi)-5-nitro-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona, [2-(2-cloro-etoxi)-5-nitro-fenil]-[4-(4-trifluorometil-feriil)-piperazin-l-il]-metanona e [5-nitro-2-(2,2,3,3,3-pentafluoro-propoxi)-fenil]-[4-(4-trifluorometil-fenil)-piperazin-l-il]-metanona.Compounds of formula I according to claim 8, characterized in that said compounds are represented by 1- (3-fluoro-4- {4- [2- (2-methoxyethoxy) -5-nitro-benzoyl] -piperazin-1-yl} -phenyl) -ethanone, (2 "isopropoxy-5-nitro-phenyl) - [4- (4-trifluoromethylphenyl) piperazin-1-yl ] -methanone. : (2-cyclopropylmethoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclobutylmethoxy-5-nitro-phenyl) - [ 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-butoxy-5-nitro-phenyl) - [4- [4-trifluoromethyl-phenyl) -piperazin-1-yl ] -methanone, [2- (2,2-dimethyl-propoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, isobutoxy-5-nitro-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (2-cyclopentyloxy-5-nitro-phenyl) - [4- (4- trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, (5-nitro-2-propoxy-phenyl) - [4- (4-trifluoromethyl-phenyl) -piperazin- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, Rac- (2-sec-butoxy-5-nitro-phenyl) - [4- (4-cyclobutoxy-5-nitro- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, 14 [5-nitro-2- (2,2,2,3,3-tetrafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl ) -piperazin-1-yl] -methanone, [5-nitro-2- (2,2,2-trifluoro-ethoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin- 1-yl] -methanone, [2- (bicyclo [2.2.1] hept-2-yloxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] (2-chloroethoxy) -5-nitro-phenyl] - [4- (4-trifluoromethyl-feryl) -piperazin-1-yl] -methanone and [5-nitro-2- (2,2,3,3 , 3-pentafluoro-propoxy) -phenyl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone. 10. Compostos dé fórmula I, de acordo com a reivindicação 1, caracterizados pelo facto de Ar representar fenilo substituído, R2 representar alquilo Ci-Cç; alquilo Ci-C6 substituído por halogéneo, (CH2)n~cicloalquilo ^3-07^ e R5 representar S(0)2NHCH3.Compounds of formula I according to claim 1, wherein Ar is substituted phenyl, R 2 is C 1 -C 6 alkyl; halogen substituted C 1 -C 6 alkyl, (CH 2) n cycloalkyl, and R 5 is S (O) 2 NHCH 3. 11. Compostos de fórmula I, de acordo com a reivindicação 10, caracterizados pelo facto de esses compostos serem representados por 3-4-{4-Ciano-3-fluoro-fenil)-piperazina-l-carbonil]-N-metil-4-trifluorometoxi-benzeno-sulfonamida, 3-[4-(4-ciano-3-fluoro-fenil)-piperazina-l-carbonil]-4-isobutoxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-3-fluoro-fenil)-piperazina-l-carbonil]-4-ciclopentiloxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-3-fluoro-fenil)-piperazina-l-carbonil]-4-ciclobutoxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-3-fluoro-fenil)-piperazina-l-carbonil]-4-ciclobutilmetoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-ciano-fenil)-piperazina-l-carbonil] -4-isobu-toxi-N-metil-benzeno-sulfonamida, I 15 3-[4-(4-ciano-fenil·)-piperazina-l-carbonil]-4-ciclopen-tiloxi-N-metil-benzeno-sulfonamida, 3- [4- (4-c.iano-fenil).-piperazina-l-carbonil] -4-ciclobu-tilmetoxi-N-metil-benzeno-sulfonamida, 3- [4- (4-ciano-2-fluoro-fen.il) -piperazina-l-carbonil] -4-isobutoxi-N-metil-benzeno-sulfonamida, 3- [4- (4-ciano-2-fluoro-fenil).-piperazina-l-carbonil J- 4- (2,2-dimetil-propoxi)-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazina-l-carbonil]-4-isopropoxi-N-metil-benzeno-sulfonamida, 3- [4- {4-ciano-2-fluoro-fen.il) -piperazina-l-carbonil] -4-. ciclopentiloxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazine-l-carbonil]-4-ciclobutoxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazina-l-carbonil]-4-çiclopropilmetoxi-N-metil-benzeno-sulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazina-l-carbonil]-4-ciclobutilmetoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazina-l-carbonil]- 4- isobutoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazina-l-carbonil]- 4- {2,2-dimetil-propoxi)-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazina-l-carbonil]- 4- ciclopentiloxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil)-piperazina-l-carbonil]- 4- ciclobutoxi-N-metil-benzeno-sulfonamida, 3- [4-(4-acetil-2-fluoro-fenil) -piperazina-l-carbonil] - 4- ciclopropilmetoxi-N-metil-benzeno-sulfonamida, 4-isobutoxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazina-l-carbonil] -benzeno-sulfonamida, 4-(2,2-dimetil-propoxi)-N-metil-3-[4-(4-trifluorometil-fenil)-piperazinà-l-carbonil]-benzeno-sulfonamida, 4-isopropoxi-N-metil-3-[4-(4-trifluorometil-fenil)-pi-perazina-l-carbonil]-benzeno-sulfonamida, 16 4-ciclopentiloxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazina-l-carbonil]-benzeno-sulfonamida, 4-ciclobutoxi-N-metil-3-[4-(4-trifluorometil-fenil)-piperazina-l-carbonil] -benzeno-sulfonamida, 4-ciclopropilmètoxi-N-metil-3-[4-(4-trifluorometil-fe-nil)-piperazina-l-carbonil]-benzeno-sulfonamida, 4-ciclobutil-metoxi-N-metil-3-[4- (4-trifluorometil^fe-nil)-piperazina-l-carbonil]-benzeno-sulfonamida, N-metil-3-[4-(4-trifluorometil-fenil)-piperazina-l-carbonil] -4-(3,3,3-trifluoro-propoxi)-benzenesulfonamida, 3-[4-(4-ciano-2-fluoro-fenil)-piperazina-l-carbonil]-N-metil-4-(2,2,2-trifluoro-etoxi)-benzeno-sulfonámida, N-metil-4- (2,2,2-trifluoro-etoxi) -3- [4- ( 4'-trif íuorome-til-fenil)-piperazina-l-carbonil]-benzeno-sulfonamida, rac-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi)-3-(4- (4--trifluorometil-fenil)-piperazina-l-carbonil]-benzeno- sulfonamida, rac-3-[4-(4-ciano-2,5-difluoro-fenil)-piperazina-l-car-bonil]-N-metil-4-(2,2,2-trifluoro-l-metil-etoxi)-benzeno-sulfonamida e rac-3-[4-(4-ciano-2,3-difluoro-fenil)-piperazina-l-carbonil] -N-metil-4- (2,2 , 2-trifluoro-l-metil-etoxi) -benzeno-sulfonamida.Compounds of formula I according to claim 10, characterized in that these compounds are represented by 3-4- (4-Cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -N-methyl- 4-trifluoromethoxy-benzenesulfonamide, 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl-benzenesulfonamide, 3- [4- 4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1 3- [4- (4-cyano-3-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutylmethoxy-N-methyl-benzene- sulfonamide, 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4-isobutyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano- ) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-phenyl) -piperazine-1-carbonyl] -4- N-methyl-benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy-N-methyl-benzene o-sulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2,2-dimethyl-propoxy) -N-methyl-benzenesulfonamide, - [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isopropoxy-N-methyl-benzenesulfonamide, 3- [4- {4-cyano-2-fluoro- yl) -piperazine-1-carbonyl] -4- cyclopentyloxy-N-methylbenzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide, 3- [4- - (4-cyano-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopropylmethoxy-N-methyl-benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl) -piperazine carbonyl] -4-cyclobutylmethoxy-N-methylbenzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-isobutoxy- benzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4- (2,2-dimethyl-propoxy) -N-methyl-benzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopentyloxy-N-methyl-benzenesulfonamide, 3- [4- (4-acetyl- piperazin-1-carbonyl] -4-cyclobutoxy-N-methyl-benzenesulfonamide, 3- [4- (4-acetyl-2-fluoro-phenyl) -piperazine-1-carbonyl] -4-cyclopropylmethoxy- methyl-benzenesulfonamide, 4-isobutoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4- (2,2-dimethyl-propoxy) - N-me 3- [4- (4-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -benzenesulfonamide, 4-isopropoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine 1-carbonyl] -benzenesulfonamide, 4-cyclopentyloxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4-cyclobutoxy-N-methyl -3- [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, 4-cyclopropylmethoxy-N-methyl-3- [4- (4-trifluoromethyl-phenyl) -piperazine- 1-carbonyl] -benzenesulfonamide, 4-cyclobutyl-methoxy-N-methyl-3- [4- (4-trifluoromethylphenyl) -piperazine-1-carbonyl] -benzenesulfonamide, N-methyl-3- - [4- (4-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -4- (3,3,3-trifluoro-propoxy) -benzenesulfonamide, 3- [4- (4-cyano-2-fluoro-phenyl ) -piperazine-1-carbonyl] -N-methyl-4- (2,2,2-trifluoro-ethoxy) -benzenesulfonamide, N-methyl-4- (2,2,2-trifluoro-ethoxy) -3- - [4- (4'-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -benzenesulfonamide, rac-N-methyl-4- (2,2,2-trifluoro-1-methyl-ethoxy) -3- (4- (4-trifluoromethyl-phenyl) -pi 1-carbonyl] benzenesulfonamide, rac-3- [4- (4-cyano-2,5-difluoro-phenyl) -piperazine-1-carbonyl] -N-methyl- 2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide and rac-3- [4- (4-cyano-2,3-difluoro-phenyl) -piperazine-1-carbonyl] -N-methyl-4- - (2,2,2-trifluoro-1-methyl-ethoxy) -benzenesulfonamide. 12. Compostos de fórmula I, de acordo com a reivindicação 1, caracterizados pelo facto de Ar representar um grupo heteroarilo com 6 átomos no núcleo, contendo um, dois ou três átomos de azoto, R2 representar alquilo C5.-C6 ou (CH2) n-cicloalquilo C3-C7 e R5 representar SO2CH3.Compounds of formula I according to claim 1, wherein Ar is a 6-membered heteroaryl group containing one, two or three nitrogen atoms, R 2 is C 5 -C 6 alkyl or (CH 2) n-C 3 -C 7 cycloalkyl and R 5 is SO 2 CH 3. 13. Compostos de fórmula I, de acordo com a reivindicação 12, caracterizados pelo facto de esses compostos serem representados por 17 [4-(3--cloro-5-trif luorometil-piridin-2-il)-piperazin-1-il]-(2-ciclopropilmetoxi-5-metano-sulfonil-fenil)-metanona, 6-[4-(2-ciclopentiloxi-5-metano-sulfonil-benzoil)-piperazin-l-il] -nicotinonitrilo, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(5-tri-fluorometil-piridín-2-íl)-piperazin-l-il]-metanona, [4-(3-cloro-5-trifluorometil-piridin-2-il)-piperazín-1 -il]-(2-ciclopentiloxi-5-metano-sulfonil-fenil)-metanona, (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(6-tri-fluorometil-piridin-3-il)-piperazin-l-il]-metanona, [4-(3-fluoro-5-trifluorometíl-piridin-2-il)-piperazin-l-il] -(2-isopropoxi-5-metano-sulfonil-fenil) -metanona e (2-ciclopentiloxi-5-metano-sulfonil-fenil)-[4-(3-fluo-ro-5-trifluorometil-piridin-2-il)-piperazin-l-il]-metanona.Compounds of formula I according to claim 12, characterized in that said compounds are represented by 17β- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl ] - (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl) -methanone, 6- [4- (2-cyclopentyloxy-5-methanesulfonyl-benzoyl) -piperazin-1-yl] -nicotinonitrile, (2-cyclopentyloxy -5-methanesulfonyl-phenyl) - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone, [4- (3-chloro-5-trifluoromethyl- 2-yl) -piperazin-1-yl] - (2-cyclopentyloxy-5-methanesulfonyl-phenyl) -methanone, (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (6- fluoromethyl-pyridin-3-yl) -piperazin-1-yl] -methanone, [4- (3-fluoro-5-trifluoromethylpyridin-2-yl) -piperazin-1-yl] - (2-isopropoxy-5- methanesulfonyl-phenyl) -methanone and (2-cyclopentyloxy-5-methanesulfonyl-phenyl) - [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin- ] -methanone. 14. Compostos de fórmula I de acordo com a reivindicação 1, caracterizados pelô facto de Ar representar um grupo de heteroarilo de 6 átomos no núcleo, contendo um, dois ou três átomos de azoto, . R2 representar alquilo Ci-Cg substituído por halogéneo e R5 representar S02CH3.Compounds of formula I according to claim 1, characterized in that Ar represents a 6-membered heteroaryl group containing one, two or three nitrogen atoms. R 2 is C 1 -C 6 alkyl substituted by halogen and R 5 is SO 2 CH 3. 15. Compostos de fórmula I, de acordo com a reivindicação 14, caracterizados pelo facto de esses compostos serem representados por rac-[4-(3-cloro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoro-l-me-tiletoxi)-fenil]-metanona, rac-[5-metano-sulfonil-2-(2,2,2-trifÍuoro-1-metil-etoxi)-fenil]-[4-(5-trifluorometil-piridin-2-il)-pipe-razin-l-il]-metanona, 18 rac-[4-(5-bromo-piridin-2-il)-piperazin-l-il]-[5-metano-sulfonil-2- (2,'2,2-trifluoro-l-metil-etoxi) -fenil] -metanona, raç-[4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il] -[5-metano-sulfonil-2-(2,2,2-trifluoro-l-me- . tiletoxi)-fenil]-metanona, rac-[5-metano-sulfonil-2-(2,2,2-trifluoro-l-metil-etoxi) —fenil]-[4-(6-trifluorometil-piridin-2-il)-piperazin-l-il] -metanona, [5-metano-sulfonil-2-((S ou R) -2,2,2-trifluoro-l-metil-etoxi)-fenil]-[4-(5-trifluorometil-piridin-2-il)-piperazin-l-il] -metanona, [ 5-metano-sulfonil-2-((R ou S)-2,2,2-trifluoro-l-metil-etoxi) -fenil]- [4-(5-trifluorometil-piridin-2-il)-piperazin-l-il.]-metanona, [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-1 -il] -[5-metano-sulfonil-2-{(S)-2,2,2-trifluoro-l-metil- . etoxi)-fenil]-metanona e [4-(3-fluoro-5-trifluorometil-piridin-2-il)-piperazin-l-il] - [5-metâno-sulfonil-2-(2,2,2-trifluoro-l,1-dimetil-etoxi)-fenil]-metanona.Compounds of formula I according to claim 14, characterized in that these compounds are represented by rac- [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methylethoxy) -phenyl] -methanone, rac- [5-methanesulfonyl-2- (2,2,2-trifluoro- -1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone, rac- [4- (5-bromo-pyridin- 2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, 5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyltetoxy) -phenyl] - methanone, rac- [5-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (6-trifluoromethyl-pyridin-2-yl) -piperazin-1 -yl] -methanone, [5-methanesulfonyl-2 - ((S or R) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- (5-trifluoromethyl- 2-yl) -piperazin-1-yl] -methanone, [5-methanesulfonyl-2 - ((R or S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] - [4- - (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone, [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin- 2 - {(S) -2,2,2-trifluoro-1-methyl-. ethoxy) -phenyl] -methanone and [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] - [5-methanesulfonyl-2- (2,2,2- trifluoro-1,1-dimethyl-ethoxy) -phenyl] -methanone. 16. Processo para a preparação de um composto de. fórmula geral I, de acordo com a reivindicação 1, processo esse caracterizado por compreender a) a reacção de um composto de fórmula .A process for the preparation of a compound of. general formula I according to claim 1, which process comprises a) reacting a compound of formula. com um composto de fórmula 19 Iwith a compound of formula I III na presença de um agente de activação tal como TBTU (2-(lH-benzotriazole-l-il)-1,1,3,3-tetrametilurónio-tetrafluoroborato)' . para se obter um composto de fórmulaIII in the presence of an activating agent such as TBTU (2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate). to provide a compound of formula (I) em que os substituintes têm os significados definidos antes ou b) a reacção de um composto de fórmula(I) wherein the substituents are as defined above or b) reacting a compound of formula 17. Composto de acordo com a reivindicação 1, quando preparado por um processo conforme reivindicado na reivindicação 16.A compound according to claim 1, when prepared by a process as claimed in claim 16. 18. Medicamento, caracterizado por conter um ou mais com postos, de acordo com a reivindicação 1 ou contendo 4- (3-amin.o-4-nitrofenil) -1-[4-(dimetilamino)-2-metoxi- 5- nitrobenzõil]-2-metil-piperazina, 1-[4-(dimetilamino) &quot;-2-metoxi-5-nitrobenzoil] -2-metil-4-(4-nitrofenil)-piperazina, 4- [4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-1-(4-nitrofenil)-piperazina, 1-(2-cloro-4-nitrofenil)-4-[4-(dimetilamino)-2-metoxi- 5- nitrobenzoil]-piperazina, 1- [4-(dimetilamino) -2-metoxi-5-nitrobenzoil] -“4-(2,4-dinitrofenil)-2-metil-piperazina, 1-(4-cloro-2-nitrofenil)-4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-piperazina e 4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-1-(2,4-dinitrofenil)-2-metil-piperazina.A medicament comprising one or more compounds according to claim 1 or containing 4- (3-amino-4-nitrophenyl) -1- [4- (dimethylamino) -2-methoxy-5- nitrobenzyl] -2-methyl-piperazine, 1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl-4- (4-nitrophenyl) piperazine, 4- [4- ) -2-methoxy-5-nitrobenzoyl] -2-methyl-1- (4-nitrophenyl) piperazine, 1- (2-chloro-4-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy- 5-nitrobenzoyl] -piperazine, 1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -4- (2,4-dinitrophenyl) -2-methylpiperazine, 1- (4-chloro-2- 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -1- (2,4-dinitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] ) -2-methyl-piperazine. 19. Medicamento de acordo com a reivindicação 18, .caracterizado pelo facto de se destinar ao tratamento de doenças à base do inibidor da absorção de glicina. 26 IA medicament according to claim 18 which is for the treatment of diseases based on the glycine absorption inhibitor. 26 I 20. Medicamento de· acordo com a reivindicação 19, caracte-rizado pelo facto de as doenças serem psicoses, dor, disfunção da memória e da aprendizagem, esquizofrenia, demência e outras doenças em que estão envolvidos processos tais como distúrbios de déficit de atenção ou doença de Alzheimer.A medicament according to claim 19, characterized in that the diseases are psychoses, pain, dysfunction of memory and learning, schizophrenia, dementia and other diseases in which processes such as attention deficit disorders or Alzheimer's disease. 20 com um composto de fórmula R2OH eventualmente na presença de um catalisador, tal como Cu (II) e uma base como carbonato de potássio, carbonato de césio ou de sódio para se obter um composto de fórmulaWith a compound of formula R 2 OH optionally in the presence of a catalyst such as Cu (II) and a base such as potassium carbonate, cesium or sodium carbonate to give a compound of formula em que X representa halogéneo e os outros substitu-intes têm os significados definidos antes ou c) a reacção de um composto de fórmulawherein X is halogen and the other substituents are as defined above, or c) reacting a compound of formula VI com um composto de fórmula R2X 21 na presença de uma base ê eventualmente na presença de micro-ondas para se obter um composto de fórmulaVI with a compound of the formula R 2 X 2 in the presence of a base is optionally in the presence of microwaves to provide a compound of formula em que X representa halogéneo, mesilato ou triflato e os outros suhstituintes têm os significados definidos antes ou d) a reacção de um composto de fórmulawherein X represents halogen, mesylate or triflate and the other substituents are as defined above or d) reacting a compound of formula R2OH em condições de Mitsunobu na presença de uma fosfonina para se obter um composto de fórmula 22R2OH under Mitsunobu conditions in the presence of a phosphonine to give a compound of formula 22 em que os substituintes têm os significados definidos antes ou e) a reacção de um composto de fórmulawherein the substituents are as defined above or e) reacting a compound of formula I I ! ArX para se obter um composto de fórmulaI I! ArX to obtain a compound of formula em que X representa um halogéneo e os outros substi tuintes têm os significados definidos antes ou í 23 f) a reacção de um composto de fórmulawherein X represents a halogen and the other substituents have the meanings defined above or (f) reacting a compound of formula Ia com uma amina ou um álcool correspondentes, na presença de um agente de activação par se obter um composto de fórmulaIa with a corresponding amine or alcohol, in the presence of an activating agent to obtain a compound of formula em que R9 representa alquilo Ci-C6, cicloalquilo C3-C6, alcoxi Ci~Cg ou NR7R8; e os outros substituintes têm os significados definidos antes ou d) a reacção de um composto de fórmulawherein R 9 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy or NR 7 R 8; and the other substituents are as defined above, or d) reacting a compound of formula com um.composto dê fórmula RONH2 para se obter um composto de fórmula 24 I Iwith a compound of formula RONH2 to give a compound of formula em que R representa H ou alquilo e os outros substitu-intes têm os significados definidos na reivindicação 1 ou h) a reacçao de um composto de fórmula I i Iwherein R 1 represents H or alkyl and the other substituents have the meanings defined in claim 1 or h) the reaction of a compound of formula I com um agente de redução como boro-hidreto de sódio (quando R representa H) ou um agente de alquilação como alquil-litio (quando R representa alquilo} para se obter um composto de fórmula i j I \with a reducing agent such as sodium borohydride (when R represents H) or an alkylating agent such as alkyl lithium (when R is alkyl) to give a compound of formula 25 em que R representa hidrogénio ou alquilo e os outros substituintes têm os significados definidos na reivindicação 1 e se desejado, a conversão dos compostos obtidos, em sais de adição de- ácidos aceitáveis sob o ponto de vista farmacêutico.In which R represents hydrogen or alkyl and the other substituents have the meanings defined in claim 1 and if desired, the conversion of the obtained compounds into pharmaceutically acceptable acid addition salts. 21. Utilização de um ' composto, tal como reivindicado na reivindicação 1 ou de um dos seguintes compostos 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-{3-clorofe-nil) -piperazina., 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-(4-fluorofe-nil)-piperazina, 1-[5-(amino-sulfonil)-2-metoxibenzoil]-4-[3-(trifluoro-metil)fenil]-piperazina, 4- (3-amino-4-nitrofenil) -1- [4-'(diitietÍlamino) -2-metoxi- 5- nitrobenzoil]-2-metilpiperazina, 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-4-(4-nitrofenil)-piperazina, 4- [4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-2-metil-l-(4-nitrofenil)-piperazina, 1-(2-cloro-4-nitrofenil)-4-[4-(dimetilamino)-2-metoxi- 5- nítrobenzoil] -piperazina,· 1-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-4-(2,4-di-nitrofenil)-2-metil-piperazina, 1-(4-cloro-2-nitrofenil)-4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-piperazina e 4-[4-(dimetilamino)-2-metoxi-5-nitrobenzoil]-1-(2,4-dinitrofenil)-2-metil-piperazina. para a ' produção de medicamentos para o tratamento de psicoses, dor, disfunção neuro-degenerativa na memória e na aprendizagem, esquizofrenia, demência e outras 27 doenças em que estão envolvidos processos cognitivos tais como distúrbios de déficit de atenção ou doença de Alzheimer. Lisboa/ 25 de Fevereiro de 2008 2EUse of a compound as claimed in claim 1 or one of the following compounds 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (3-chloro-phenyl) -piperazine. - [5- (aminosulfonyl) -2-methoxybenzoyl] -4- (4-fluorophenyl) piperazine, 1- [5- (aminosulfonyl) -2-methoxybenzoyl] -4- [3- (trifluoro 4- (3-amino-4-nitrophenyl) -1- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methylpiperazine, 1- [4- (dimethylamino- ) -2-methoxy-5-nitrobenzoyl] -2-methyl-4- (4-nitrophenyl) piperazine, 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -2-methyl- 4-nitrophenyl) piperazine, 1- (2-chloro-4-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] piperazine, 1- [4- (dimethylamino) -2- methoxy-5-nitrobenzoyl] -4- (2,4-di-nitrophenyl) -2-methylpiperazine, 1- (4-chloro-2-nitrophenyl) -4- [4- (dimethylamino) -2-methoxy -5-nitrobenzoyl] -piperazine and 4- [4- (dimethylamino) -2-methoxy-5-nitrobenzoyl] -1- (2,4-dinitrophenyl) -2-methylpiperazine. for the production of medicaments for the treatment of psychoses, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes such as attention deficit disorders or Alzheimer's disease are involved. Lisbon / February 25, 2008 2E
PT04763703T 2003-08-11 2004-08-02 Piperazine with or-substituted phenyl group and their use as glyt1 inhibitors PT1656361E (en)

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